Note: Descriptions are shown in the official language in which they were submitted.
24205-912
The present invention relates to novel condensed
heterocyclic compounds or their salts. The compounds of the
invention are useful as a medicine and a cholinesterase inhibitor
and specifically as a therapeutic or/and prophylactic agent for
senile dementia, Alzheimer's disease and so on.
In these days of aging society, there have been pro-
posed a variety of compounds which have therapeutic and prophy-
lactic efficacy for senile dementia. It has been found that
physostigmine, a naturally-occurring cholinesterase inhibitor, has
therapeutic and/or prophylactic activity for senile dementia.
However, physostigmine has the drawbacks of a short duration of
action, high toxicity and so on.
Meanwhile, as synthetic; drugs for a colinesterase
inhibitor, depressant or so, a variety of heterocyclic compounds
have been proposed (e. g. United States Patent 4,064,255, United
States Patent 4,208,417, United States Patent 4,849,431, United
States Patent 4,895,841, Japanese Published Unexamined Patent
Application No. 169569/1990 and EP-A-0,378,207).
However, what is needed now is a compound which is
more active, longer-acting and less toxic than the compounds
already known to have therapeutic and/or prophylactic efficacy
for senile dementia.
The present invention provides a novel class of com-
pounds which are useful as a cholinesterase inhibitor and
particularly as a therapeutic and/or prophylactic agent for senile
dementia, Alzheimer's disease and so on.
- 1 -
2~~~~~~
24205-912
The inventors of present invention explored com-
pounds which could be of use as medicament for improving the
functions of the central nervous system and particularly compounds
of value for the relief of senile dementia, Alzheimer's disease
and so on due to brain ischemia and succeeded in the creation of
a condensed heterocyclic compound of the formula:
/ (CH2 ) k / O 2
X A ~ C- (CH2 ) n 'N-R ( I )
~ (CH2 ) m
[wherein X is an oxygen atom, a sulfur atom or R1-NG wherein R1
is a hydrogen atom, a hydrocarbon group which may be substituted
or an acyl group which rnay be substituted; R2 is a hydrogen atom
or a hydrocarbon group which may be substituted; ring A is a
benzene ring which may be substituted; k is an integer of 0 to 3;
m is an integer of 1 to 8; and n is an integer of 1 to 6], or a
salt thereof.
The compound (I) o.r its salt according to the present
invention is structurally characterized in that the hetero atom
(O, S or N)-containing heterocycle fused to the benzene ring is
a saturated ring and that a substi.tuent group of the formula:
-CO(CH2)n ~N_R2
is bound directly to a carbon atom of the benzene ring. This
compound is believed to be a novel compound which has not been
disclosed in the literature.
Referring to the above formula (I), the "hydrocarbon
- 2 -
~~j~°~ ~'
24205-912
group" of "the hydrocarbon group which may be substituted" as
designated by R1 and R2 includes acyclic, cyclic, saturated, un-
saturated or their optionally combined hydrocarbon groups.
The acyclic saturated hydrocarbon group includes
straight-chain or branched Cl-11 a7.kyl groups (e. g. methyl, ethyl,
n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl,
n-hexyl).
The acyclic unsaturated hydrocarbon group includes
straight-chain or branched C2-4 alkenyl groups (e. g. vinyl, allyl,
2-butenyl) and C2-4 alkynyl groups (e. g. propargyl, 2-butynyl).
The cyclic saturated hydrocarbon group includes
C3-~ monocyclic cycloalkyl groups (e. g. cyclobutyl, cyclopentyl,
cyclohexyl) and C$-14 bridged cyclic saturated hydrocarbon groups
(e. g. bicyclo[3.2.1]oct-2-yl, bicyclo[3.3.1]non-2-yl, adamantan-
1-yl) .
The cyclic unsaturated hydrocarbon group includes
phenyl, naphthyl and so on.
The "hydrocarbon group" of the "hydrocarbon group
which may be substituted" as designated by Rl and R2 may be an
optionally combined hydrocarbon group representing an optional
combination of the above-mentioned acyclic, cyclic, saturated and
unsaturated hydrocarbon groups, such as C~-18 aralkyl (such as
phenyl C1-12 alkyl and naphthyl Cl-8 alkyl, e.g. phenylmethyl,
phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl,
(x-naphthylmethyl), C8-1$ a.rylalkenyl (such as aryl C2-12 alkenyl,
e.g. styryl, cinnamyl, 4-phenyl-2-butenyl, 4-phenyl-3-butenyl),
- 3 -
24205-912
C8-1$ arylalkynyl (such as aryl 02_12 alkynyl, e.g. phenyl-
ethynyl, 3-phenyl-2-propynyl, 3-phenyl-propynyl), C3-~ cycloalkyl-
C1-6 alkyl (e. g. cyclopropylmethyl, cyclobutylmethyl, cyclopentyl-
methyl, cyclohexylmethyl, cyclohept.ylmethyl, cyclopropylethyl,
cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptyl-
ethyl, cyclopropylbutyl, cyclobutyl.butyl, cyclopentylbutyl,
cyclohexylbutyl, cycloheptylbutyl, cyclopropylpentyl, cyclobutyl-
pentyl, cyclopentylpentyl, cyclohexylpentyl, cycloheptylpentyl,
cyclopropylhexyl, cyclobutylhex:yl, cyclopentylhexyl, cyclohexyl-
hexyl, cycloheptylhexyl) groups and so on.
The preferable examples of the "hydrocarbon group"
of the "hydrocarbon group which may be substituted" as designated
by Rl include a straight-chain or branched Cl-~ alkyl group (e. g.
methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl,
n-pentyl, n-hexyl) or a C~-10 aralkyl group (e. g. phenylmethyl,
phenylethyl, phenylpropyl) and the preferable examples of the
"hydrocarbon group" of the "hydrocarbon group which may be sub-
stituted" as designated by R2 include a C~-10 aralkyl (e. g.
phenylmethyl, phenylethyl, phenylp:ropyl).
The acyclic saturated, acyclic unsaturated and cyclic
saturated hydrocarbon groups mentioned above for Rl and R2 may
be substituted by 1 to 5 substituents selected from the group
consisting of halogen (e. g. fluoro, chloro, bromo, iodo), nitro,
cyano, hydroxy, Cl-4 alkoxy (e. g. methoxy, ethoxy, propyloxy,
butyloxy, isopropyloxy), Cl-4 ;~lkylthio (e. g. methylthio, ethyl-
thio, propylthio), amino, mono- or di-Cl-4 alkyl-substituted
- 4 -
2~j~~~°~'~
24205-912
amino (e. g. methylamino, ethylamino, propylamino, dimethylamino,
diethylamino), cyclic amino (e. g. pyrrolidino, piperidino,
morpholino), C1-4 alkylcarbonylamino (e. g. acetylamino, propionyl-
amino, butyrylamino), C1-4 alkylsu:lfonylamino (e. g. methyl-
sulfonylamino, ethylsulfonylami_no), C1-4 alkoxycarbonyl (e. g.
methoxycarbonyl, ethoxycarbonyl, p:ropoxycarbonyl), hydroxycarbonyl,
C1-6 alkylcarbonyl (e. g. methylcarbonyl, ethylcarbonyl, propyl-
carbonyl), carbamoyl, mono- or di-C1-4 alkyl-substituted carbamoyl
(e. g. methylcarbamoyl, ethylcarbamoyl), C1-6 alkylsulfonyl
(e.g. methylsulfonyl, ethylsulfonyl, propylsulfonyl) and so on.
The substituents on the "benzene ring which may be
substituted" as designated by ring A in formula (I) and the
substituents on the cyclic unsaturated hydrocarbon group as
designated by R1 and R2 include C1-4 alkyl (e. g. methyl, ethyl,
propyl, butyl), halogen (e. g. fluoro, chloro, bromo, iodo), nitro,
cyano, hydroxy, C1-4 alkoxy (e. g. methoxy, ethoxy, propyloxy,
butyloxy,
- 4a -
~~~'~~~ ~~~
e.J ~ r.
24205-912
isopropyloxy ) , C1_~ alkyltriio ( a . g . methylthio,
ethylthio, propylthio, isopropylthio, butylthio),
amino, mono- or di-C,_4 alkyl-substituted amino (e. g.
methylamino, ethylamino, propylamino, dimethylamino,
diethylamino), cyclic amino(e.g. pyrrolidino,
piperidino, morpholino), C1_4 alkylcarbonylamino (e. g.
acetylamino, propionylamino, butyrylamino},
aminocarbonyloxy, mono- or di-C~~ alkyl-substituted
aminocarbonyloxy {e. g. methylaminocarbonyloxy,
ethylaminocarbonyloxy, dimethylaminocarbonyloxy,
diethylaminocarbonyloxy), C1_4 alkylsufonylamino (e. g.
methylsulfonylamino, ethylsulfonylamino,
propylsulfonylamino) , C~_4 alkoxycarbonyl (e.g.
metoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isobutoxycarbonyl), hydroxycarbonyl, C,_6 alkylcarbonyl
(e. g. methylcarbonyl, ethylcarbonyl, butylcarbonyl),
C_o cycloalkylcarbonyl (e. g. cyclohexylcarbonyl),
carbamoyl, mono- or di-C;_" alkyl-substituted carbamoyl
(e. g. methy_Lcarbamoyi, ethylcarbamoyl, propylcarbamoyl,
butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl) and
C1_b alkylsulfonyl (e.:~. methy.lsulFonyl, ethylsulfonyl,
propylsulfonyl) andC3~ccycloalkvylsulfonyl (e.g. cyclo-
pentylsulfonyl, cyclohexylsulfonyl) as well as a phenyl,
naphthyl, phenoxy, benzoyl, phenoxycarbonyl, phenyl-C~_,;
alkylcarbamoyl (e. g. phenylmethylcarbamoyl,
phenylethylcarbamoyl, phenylpropylcarbamoyl),
phenylcarbamoyl , phenyl-Ci_:, a.lk~alcarbonylamino ( a . g .
phenylmethylcarbonylamino, phenylethylcarbonylamino),
benzoylamino, phenyl-C1_4 alky.lsulfonyl (e. g.
phenylmethylsulfonyl, phenylethylsulfcnyl), phenyl-
sulfonyl, phenyl-C,_4 alkylsul:finyl (e.g.
phenylmethylsulfinyl, phenylethylsulfinyl), phenyl-C1_4
alkylsulfonylamino (e. g. phenylmethylsulfonylamino,
phenylethylsulfonylamino) or phenylsulfonylamino which
may have 1 to 4 substituents, for example selected from
-5-
d
24205-912
the group consisting of Cl._4 alkyl groups such as
methyl, ethyl, propyl, butyl, isopropyl, etc., C1_4
alkoxy groups such as methoxy, ethoxy, n-propyloxy, i-
propyloxy, n-butyloxy, etc., halogen such as chloro,
bromo and iodo, hydroxy, benzyloxy, amino, mono- or di-
CL_~ alkyl- substituted amino such as mentioned above,
nitro, and C1_6 alkylcarbonyl ouch as mentioned above
and so on. The appropriate number of such substituents
on the benzene ring or cyclic unsaturated hydrocarbon
group is 1 to 3.
The optionally combined hydrocarbon group as
designated by R1 and R2 may be substituted by 1 to 5
substituents selected from the group consisting of C1_4
alkyl {e. g. methyl, ethyl,, propyl, butyl), halogen.
(e. g. fluoro, chloro, bromo, iodo), vitro, cyano,
hydroxy, C1_; alkoxy (e. g. methoxy, ethoxy, propyloxy,
butyloxy, isopropyloxy ) , C., _4 alkylthio ( a . g .
methylthio, ethylthio, propylthio, isopropylthio,
butylthio), amino, mono- or di-C,_4 alkyl-substituted
amino (e.g. methylamino, ethylamino, propylamino, di-
methylamino, diethylamino), cyclic amino (e. g.
pyrrolidino, piperidino, morpholino), C,_~
alkylcarbonylamino (e. g. acetylamino, propionylamino,
butyrylamino), aminocarbonylo:xy, mono- or di-C1_~ alkyl-
substituted aminocarbonyloxy (e. g.
methylaminocarbonyloxy, et:hylaminocarbonyloxy,
dimethylaminocarbonyloxy, diethylaminocarbonyloxy), C1_4
alkylsufonylamino (e. g. methylsulfonylamino, ethylsul-
fonylamino, propylsulfonylami:no), C:_4 alkoxycarbonyl
(e. g. metoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isobutoxycarbonyl), hydroxyca:rbonyl, C,_6 alkylcarbonyl
(e. g. methylcarbonyl, ethylca:rbonyl, butylcarbonyl),
C3_6 cycloalkylcarbony.l (e. g. cyclohexylcarbonyl),
carbamoyl, mono- or di-C1_~, alkyl-substituted carbamoyl
{e. g. methylcarbamoyl, etriylc,arbamoyl, propylcarbamoyl,
-6-
24205-912
butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl).
C1_6 alkylsulfonyl (e. g. methylsulfonyl, ethylsulfonyl,
propylsulfonyl) and C3-~ ~~ycloalkylsul.fonyl (e. g. cyclo-
pentyisulfonyl, cyclohexylsul.fonyl) as well as phenyl,
naphthyl, phenoxy, benzoyl, F>henoxycarbonyl, phenyl-C,_4
alkylcarbamoyl (e. g. phenylme~thylcarbamoyl,
phenylethylcarbamoyl, phe:nylpropylcarbamoyl),
phenylcarbamoyl, phenyl-C1_4 alkylcarbonylamino (e. g.
phenylmethylcarbonylamino, phenylethylcarbonylamino),
benzoylamino, phenyl-Cl_4 alkylsulfonyl { a . g .
phenylmethylsulfonyl, phenylethylsulfonyl), phenyl-
sulfonyl, phenyl-C1_4 alky:Lsulf inyl ( a . g .
phenylmethylsulfinyl, phenylethylsulfinyl), phenyl-C1_4
alkylsulfonylamino (e. g. phenylmethylsulfonylamino,
phenylethylsulfonylamino) or phenylsulfonylamino which
may have 1 to 4 substitue:nts, for example selected from
the group consisting of C,_;, alkyl groups such as
methyl, ethyl, propyl, butyl, isopropyl, etc., C1_4
alkoxy groups such as met.hoxy, ethoxy, n-propyloxy, i-
propyloxy, n-butyloxy, etc., halogen such as chloro,
bromo and iodo, hydroxy, benzyloxy, amino, mono- or di-
C,_4 alkyl-substituted amino such as mentioned above,
nitro, and C1_6 alkylcarbonyl such as mentioned above
and so on.
The "acyl" of the "acyl group which may be substi-
tuted" as designated by R1 includes carboxylic acid acyl
groups (e.g. formyl,C~_a alkyl- or phenyl carbonyl groups
such as acetyl, propionyl, bu~.tyryl, benzoyl, etc.),
sulfonic acid acyl groups ( a . g . C1_; alkyl- or
phenylsulfonyl grou~as such as. methanesulfonyl,
benzenesulfonyl, p-toluensulfonyl, etc.), phosphonic
acid acyl groups {e. g. CL_~ alkyl- or phenylphosphanyl
groups such as methanephosphonyl, benzenephosphonyl,
etc.), and substituted oxycarbonyl groups (e. g. Cz_8
alkyloxycarbonyl or C~_$-a_ralkyloxy-carbonyl groups such
- 7 _.
t .. r.. P .rl
Le
24205-912
as methyloxycarbonyl, tert:-butyLoxycarbonyl., benzyloxy-
carbonyl, etc.).
Each of these acyl gx-oup~s may optionally have 1 to
3, preferably 1 to 2, substituents such as halogen
(e.g. fluoro, chloro, bromo, iodo), amino, C1_6 alkyl or
C3_6 cycloalkyl-substituted primary or secondary amino
(e. g. methylamino, ethylamino, propylamino,
cyclohexylamino, dimethylamino, diethylamin.o,
diisopropylamino, dicyclohexy.lamino), C,_4 alkoxy (e. g.
methoxy, ethoxy, propoxy) and so on.
X is preferably R1-N< and especia.:ly R~ is prefer-
ably hydrogen, methyl, ethyl, benzyl, acetyl, benzoyl,
methoxycarbonyl or ethoxyc:arbonyl.
R' is preferably a benzyl. or ~-naphthylmethyl
group which is either unsubst:ituted or substituted by 1
or 2 substituents selected from the group consisting of
halogen (e.g. fluoro and chloro), methyl, nitro and
methoxy and more preferable a}samples of R2 include an
unsubstituted benzyl.
The substituent on ring :~ is preferably fluoro,
chloro, trifluoromethyl, methyl or methoxy, and more
preferably fluoro.
The preferred k and m are such that when the sum
of k and m is a whole number of 2, to 6; that is when
~- NCH Z ~ ~-
k ,
~<CH ~ ~,~
forms a 5 to 9 membered ring.
The preferred combination of k and m is such that
when k is 0, m is 2, 3, 4 or _'i; when k is 1, m is 1, 2
or 3; or when k is 2, m is 2. Thus, the preferred
nitrogen-containing condensed heterocyclic rings which
are represented by
-g_
G f, ~, ~' ~'
1 "'1 ~..: °.'~.
~~ ~f e.1 ~ >.~
( x-R1-N< )
~(CHZ)~ ~ ~
are 2,3-dihydro-1H-indole,. 1,2,3,4-tetrahydroquinoline,
2,3,4,5-tetrahydro-1H-1-benzazepine, 2,3-dihydro-1H-
isoindole, 1,2,3,4-tetrahydro.isoquinoline, 2,3,4,5-
tetrahydro-1H-2-benzazepine, 2,3,4,5-tetrah.ydro-1H-3-
benzazepine, 1,2,3,4,5,6-hexa:hydro-1-benzazccine,
1,2,3,4,5,6-hexahydro-2-bE:nzazocine, 1,2,3,4,5,6-
hexahydro-3-benzazocine, 2,3,4,5,6,7-hexahydro-1H-1-
benzazonine, 2,3,4,5,6,7-hexa:hydro-1H-2-benzazonine,
2,3,4,5,6,7-hexahydro-1H-3-benzazonine, 2,3,4,5,6,7-
hexahydro-111-4-benzazonine .
The preferred oxygen--containing condensed
heterocyclic rings which are represented by
,,CCHz~~~/'\
I
X~CC3z)~.~~~i ( x-p
are 2,3-~:ihydrobenzofuran,, i,3-d:ihydreisobenzofuran,
3,4-dihydro-2H-1-benzopyran, 2,3,4,5-t.etrahydro-1-
benzoxepin, 1,3,4,5-tetrahydro-2-benzcxepin, 1,2,4,5-
tetrahydro-3-benzoxepin, :3,4,5,5-tetrahydra-2H-1-benzo-
xocin, 3,4,5,6-tetrahydr~:~--1H-2-benzoxocin, 1.,4,5,6-
tetrahydro-2H-3-benzexocin, 2,3,4,5,6,7-hexahydro-1-
benzoxonin, 1,3,4,5,6,7-hexahydro-2-benzoxonin,
1,2,4,5,6,7-hexahydro-4-benzoxcnin, 1,2,3,5,6,7-hexa-
hydro-4-benzoxonin.
The preferred sulfur-containing condensed
heterocycli~~ rings which are represented by
~ ~CHf~'~ /
x~CCHz? ~ v ~ ( x-S )
a
are 2,3-dihydro[bJthiophe~a, 1,3-
dihydrobenzo[c]thiophen, 3,4-dih:ydro-LH-1-
benzothiopyran, 3,4-dihyd:ro-1H-2-benzothiopyran,
-9-
J
24205-912
2,3,4,5-tetrahydro-1-benzothiepin, 1,3,4,5--tetrahydro-2-benzo-
thiepin, 1,2,4,5-tetrahydro-3-benzothiepin, 3,4,5,6-tetrahydro-
2H-1-benzothiocin, 3,4,5,6-tetrahydro-1H-2-benzothiocin, 1,4,5,6-
tetrahydro-2H-3-benzothiocin, 2,3,.4,5,6,7-hexahydro-1-benzothio-
nin, 1,3,4,5,6,7 - hexahydro-2-benzothionin, 1,2,4,5,6,'7-hexa-
hydro-3-benzothionin, 1,2,3,5,6,7--hexahydro-4-benzothionin.
The more preferred hE:terocycl:ic rings which are
represented by
(CH2)k
'~ I
~ (CH2)mi
wherein each symbol is as defined above, include
H H
N~ / l~f / \ /
\ I) or R3N
r
wherein R3 is a hydrogen atom or .a C1-3 alkyl group. The Cl-3
alkyl group of R3 includes methyl, ethyl, propyl and iso-propyl.
The preferred example of n is 1, 2 or 3, and more
preferably 2.
Specifically, thE: following compounds of formula
(I) and their salts thereof are preferred.
-- 10 -
,f r-~ t. a ~ ~ ,~.
'~~ '~ ~~ ~_~= ~
f
1
X
~N~ ~. .Xa
,;r
-: v
CCH2)m,~~' ,C_ (CHZy-~ V__g2
X;~ ;~ ,,-
0
No.m' n XI Xz X3 F,~ t~z
1 I 2 H H H H CH ZPh
2 1. 2 H H H CH3 CH 2Ph
3 1 2 H H H (y;HS CH 2i'h
4 1. 2 H H H C~f~PhC~IZPh
5 1. 2 H H H (:C)CH3Cil2J'h
6 I ? H H H t:ClPhC'l~Ph
1 ~ CH3 H H (:H;3 CH~~Ph
8 I 2 H F CH:3 t;H~3 Czi~i'h
9 1. 2 H Cl H (;If3 C:~~P
h
10 1. ? CII:,OCH3 H (~f:; C~i~~'h
I1 ' '?OCHS F H (:if;;Cii~?h
12 1 2 F F H ~:rI;3Ca!
~~'h
13 1 2 OCH3 Ci H c.H,3 Clj~;'h
14 I ? F F OCH~ (:(,3 CH ~i'h
15 I 2 C1 CH3 F (:H3 CH ~Ph
16 1 2 H H H CH:3 C~~zCH~Ph
1 1. 2 H H H CH3 C~~
i ~--~'~;
'~~
F
-11--
t, na ,. ~ ~ r~
a
Na.m' n X X'' XB R' Rz
18 1 2 H H H CH2Ph C;f~z
F
19 1 2 H H H H C;~~z-'y?
F
20 1 2 H H H H C;Hz
21 1 2 H H H CH3 CHz ~,~--C1
22 1 2 H H H CH 3 C;~~z~%'~;-QC'H3
23 1 2 H H H CH3 C:H2~'~-CH3
24 1 2 CF;3 F H H C:Hz-~~~Y
F
25 1 2 Cl H H H C;il2-:~;
F
26 1 2 0CH3 F CH;; CHs C;Hz~ y
F
27 1 2 H F C1 CH3 CIIz-G
F
28 1 2 CH;, H H H CHz-~~'~~"~-F
29 I 2 tJl H H H Clfz~~?-~C'H~;
,.
30 1 2 CH,, H H C:Hz Cflz ~a-OCHz
31 1 2 F H C? CHz C;H2~~-OC;H:;
32 i 2 OCII;C1 H CH;; Cilz~'~?
~, F
33 I ? i)CIIH H CH,; C;~ z~%
; ~,
F
34 i 1 H H H H C,lfzPh
35 1 1 H H H CHI ClizPh
36 1 3 H H H H C;iIzPh
3 1 3 H H H CHI CIIzPh
i
38 0 2 H H H H CHzPh
39 0 2 H H H CH3 C;iizPh
40 0 2 H H H CzH~ CfizPh
--12 -
No.m' n X1 Xz X3 K1 Rz
41 0 2 H H H CH2Ph CHzPh
42 0 2 H H H COCH3 CHZPh
43 0 2 H H H COPh CHZPh
44 0 2 F H H CH3 CHZPh
45 0 2 F H CH3 CH3 CH2Ph
46 0 2 CH3 H H CH3 CHzPh
47 0 2 OCH3 H H CH3 CHzPh
48 0 2 C1 H H CH3 CHzPh
49 0 2 OCH3 C1 H CH3 CH2Ph
50 0 2 F H OCH3 CH3 CH2Ph
51 0 2 Cl CH3 F CH3 CHZPh
52 0 2 H H H H CHz-
~F
53 0 2 H H H CH3 CHz-
wF
54 0 2 H H H CHZPh CHz ~
F
55 0 2 H H H H CH~~~
C1
56 0 2 H H H CH,; CHZ-~'~~'~-C1
~7 Q 2 H H H GHZPh CHz-.~-Cl
58 0 2 H H H H CHT:%~F
59 0 2 H H H H CHz-
60 0 2 H H H CH3 CHz-~CH3
61 0 2 F H H H CHz~,~'
F
62 0 2 Cl H H H CH~
F
63 0 2 H H CH3 CH3 CHZ-~
F
-13-
No.m'n X1 Xz X3 E1 Rz
64 0 2 F H C1 CH3 CHz-
65 0 2 F H H H CHz \F
~OCH3
66 0 2 Cl H H H CHz--~-OCH3
67 0 2 H H CH3 CH3 CHz-~- C1
68 0 2 F H Cl CH3 CHz-~- C1
69 0 2 OCH3 OCH3 H CH3 CHz-
F
70 2 2 H H H H CHZPh
71 2 2 H H H CH3 CHZPh
72 2 2 H H H CZHS CHZPh
73 2 2 F H H H CHZPh
74 2 2 F H H CH3 CH2Ph
75 2 2 F H H CHZPh CHZPh
76 2 2 F H Cl CH3 CH2Ph
77 2 2 F H CH3 CH3 CH2Ph
78 2 2 CH3 H H CH3 CHZPh
79 2 2 OCH3 H H CH3 CHzPh
80 2 2 C1 H H CH3 CHZPh
81 2 2 OCH3 Cl H CH3 CHzPh
82 2 2 F H OCH3 CH3 CHZPh
83 2 2 C1 CH3 F CH3 CHzPh
84 2 2 H H H H CH ~
F
85 2 2 H H H CH3 CHz-
F
86 2 2 H H H CHaPh CHZ~
F
-14-
Image
~0~~~~4'~
0
\C- (CH z ) n-C1-8 z
N X~
~CHZ~m~ ~ ~X2
No. m' n X1 Xz X3 K1 Az
90 1 2 H H H H CHZPh
91 1 2 H H H CHs CH2Ph
92 1 2 H H H CZHS CHZPh
93 1 2 H H H CHZPh CH2Ph
94 1 2 H H H COCHs CHZPh
95 1 2 H H H COPh CHZPh
96 1 2 H F H CHs CHZPh
97 1 2 H F CHs CHs CHzPh
98 1 2 H OCHs OCHs CHs CHZPh
99 1 2 H F Cl CHs CHz-
F
100 1 2 H F H H CHz-~~
F
101 1 2 Cl F H H CHz-,'~
~,
~
F
102 1 2 H C1 CHs CHs CHz~
F
103 1 2 H OCHs H CHs CHz
F
104 1 1 H H H H CHZPh
105 1 1 H H H CHs CHzPh
106 1 3 H H H H CH2Ph
107 1 3 H H H CHs CHZPh
-16--
2~~~~~~'~
No.m' n X1 X2 X3 R1 Rz
1080 2 H H H H CHZPh
1090 2 H H H CH3 CH2Ph
1100 2 H H H CzHS CHZPh
1110 2 H H H CHZPh CHZPh
1120 2 H H H COCH3 CHzPh
1130 2 H H H COPh CHZPh
1140 2 H F H CH3 CHZPh
1150 2 H F CH3 CH3 CH2Ph
1160 2 H F H CH3 CHz-
F
1172 2 H OCH3 H CH3 CHZPh
1182 2 H CH3 H CH3 CHZPh
1192 2 H H H H CH z~;~
120 2 2 H H H CH3 CHz .,~
121 2 2 H H H CHzPh CH~~ F
122 2 2 H F- H CH3 CH.~~'~F
'F
~F
-17-
X1 C- CCHz)r~ ~'N-Rz
~'I
' 0
CCHz)m' X 'Xz
No. m'n X1 X2 X3 R1 gz
123 1 2 H H H H CHZPh
124 1 2 H H H CHs CHZPh
125 1 2 H H H CzHS CHZPh
126 1 2 H H H CHaPh CHZPh
127 1 2 H H H COCHs CHZPh
128 1 2 H H H COPh CHzPh
129 1 2 H H CHs CHs CHZPh
130 1 2 H F CHs GHs CHZPh
131 1 2 F H F CHs CHzPh
132 1 2 H OCHs OCHs CHs CHZPh
133 1 2 OCHsH H CHs CHZPh
134 1 2 H F F CHs CHZPh
135 1 2 OCHsC1 H CHs CHZPh
136 1 2 F H OCHs CHs CHzPh
137 1 2 C1 CHs F CHs CHzPh
138 1 2 H H H CHs CHZCHZPh
139 1 2 H H H CH CH z~
s
F
_1g_.
2~~~~~~~
No. m'n X' Xz X3 R1 Rz
140 1 2 H H H CHzPh CHz-
F
141 1 2 H H H H CH z-~-
F
142 1 2 H H H H CH
143 1 2 H H H CH3 CHzF--~-C1
144 1 2 H H H CH3 CHz--~-OCH3
145 1 2 H H H CH3 CHz-~-CH3
146 1 2 H H CH3 H CHz-
F
147 1 2 Cl H H H CHz-
F
148 1 2 H H CH3 C1~3 CHz-
F
149 1 2 H F C1 CH3 CHz-
'F
150 1 2 F H CH3 H CH ~-F
151 1 2 Cl H F I~ CHz--~"
'-OCH3
152 l 2 H H CH3 C1~3 CHz-~y-OCH3
153 1 2 F H Cl CH3 CHz-'~~-OCH3
154 1 2 H H H CIi3 H
155 1 2 H H H CHzPh H
156 1 1 H H H H CHZPh
157 1 1 H H H CH3 CHZPh
158 1 3 H H H H CHzPh
159 1 3 H H H CH3 CHZPh
160 0 2 H H H H CHzPh
161 0 2 H H H CHs CHZPh
162 0 2 H H H CzHS CHZPh
-19-
2fl~~~~~~
H0.m'n X~ Xz X3 A' R2
1630 2 H H H CHzPh CHZPh
1640 2 H H H COCHs CHZPh
1650 2 H H H COPh CHZPh
1660 2 H F H CHs CHZPh
1670 2 H F CHs CHs CHZPh
1680 2 CHs H H GHs CH2Ph
1690 2 H OCHs H GHs CHZPh
1700 2 H C1 H CHs CHZPh
1710 2 OCHsCl H CHs CHZPh
1720 2 H F OCHs CHs CHZPh
1730 2 Cl CHs F CHs CHZPh
1740 2 H H H H CHz
F
1750 2 H H H CHs CH~
wF
1760 2 H H H CHzPh CHz~'
~~F
1770 2 H H H H CHz ~~Cl
1780 2 H H H CHs CHz ~-Cl
1790 2 H H H CHZPh CHz~' ~C1
1800 2 H H H H CHz~, ~-F
1810 2 H H H H CHz
1820 2 H H H CHs CHz~CH3
1830 2 H F H H CHz
F
1840 2 H Cl H H CH z-
F
1850 2 H F CHs CHs CHz~
F
-20-
2~~~~~'~
No. m'n X1 Xz X3 R' Rz
186 0 2 F F H CHs CHz~
F
187 0 2 F H H H CHz-~-OCHs
188 0 2 C1 Cl H H CHz~OCH3
189 0 2 H F CHs CHs CHz-~-C1
190 0 2 F F H CHs CHz-~-Cl
191 0 2 H H H CHs H
192 2 2 H H H H CHZPh
193 2 2 H H H CHs CHZPh
194 2 2 H H H CzHS CHzPh
195 2 2 H H F H CHZPh
196 2 2 H H C1 CHs CHZPh
197 2 2 F H CHs CH2Ph CHZPh
198 2 2 F H Cl CHs CH2Ph
199 2 2 H H CHs CHs CHzPh
200 2 2 CH;; H H CHs CHZPh
201 2 2 OCi~aH CH;, CHs CH2Ph
202 2 2 C1 H CHs CHs CHzPh
203 2 2 OCHs Cl CHs CHs CHzPh
204 2 2 F H OCHs CHs CH2Ph
205 2 2 C1 CHs F CHs CHzPh
206 2 2 H H H H CH
F
207 2 2 H H H CHs CHz~'~
'-' F
208 2 2 H H H CH2Ph CH2 ~ F
-21-
No. m' n X' X z X 3 R' R z
209 2 2 H H CH3 H CHz~- F
210 1 2 H H H CH3 CH3
211 1 2 H H H C2H5 CZHS
212 CH3
N
CCHz)z ~N CHz~
-22-
x1
/(CHz) /Xz
R1-N,
2
\(CHz)m X3 ~-(CHz)n~N-R
0
No. k m n X' Xz X3 R' Az
213 1 2 2 H H H H CHZPh
214 1 2 2 H H H CH3 CHZPh
215 1 2 2 H H H CZHS CHZPh
216 1 2 2 H H H CHzPh CHZPh
217 1 2 2 H H H COCH3 CHZPh
218 1 2 2 H H H COPh CHZPh
219 1 2 2 H F H CH3 CHzPh
220 1 2 2 H F CH3 CH3 CHzPh
221 1 2 2 CH3 Cl H CHs CHZPh
222 1 2 ? H OCH3 H CH3 CHzPh
223 1 2 2 OCH3F H CH3 CHzPh
224 1 2 2 F F H CH3 CHZPh
225 1 2 2 C1 C1 H CH3 CHZPh
226 1 2 2 F F OCH3 CH3 CH2Ph
227 1 2 2 CI CH3 F CH3 CHZPh
228 1 2 2 H H H CH3 CHZCHzPh
229 1 2 2 H H H CH3 CHI
F
-23-
~~~~~'~ e'
lVo.km n X1 XZ X3 R1 R2
23012 2 H H H CH2Ph CH2
'F
23112 2 H H H H CH Z--~-
F
23212 2 H H H H CHZ-
23312 2 H H H CH3 CH ~- Cl
23412 2 H H H CH3 CHZ~- OCH3
23512 2 H H H CH3 CH2~-CH3
23612 2 CF3 F H H CH2-
F
23712 2 C1 C1 H H CH2
F
23812 2 H F CH3 CH3 CH2-
F
23912 2 H F C1 CH3 CHZ-
F
24012 2 CH3 H H H CHZ~- F
24112 2 C1 C1 H H CHZ-~-pC~~3
24212 2 H F CH3 CH3 CHI-~~-OCH3
24312 2 F OCH3 Cl CH3 CHz-v~~-OCH3
24412 2 H H H CHZPh H
24512 2 H H ~ H CH3 H
24612 1 H H H H CHZPh
24712 1 H H H CH3 CH~Ph
24812 3 H H H H CHZPh
24912 3 H H H CH3 CHZPh
25013 2 H H H H CH~Ph
25113 2 H H H CH3 CHzPh
25213 2 H H H CZHS CH~Ph
-24-
No.km n X1 Xz X3 g' gz
25313 2 H H H CH2Ph CH2Ph
25413 2 H H H COCH3 CHzPh
25513 2 H H H COPh CHzPh
25613 2 CH3 H H CH3 CHZPh
25713 2 CH3 H CH3 CH3 CHZPh
25813 2 F F H CH3 CHZPh
25913 2 OCH3 H H CH3 CH2Ph
26013 2 C1 H H CH3 CHZPh
26113 2 OCH3 C1 H CH3 CHZPh
26213 2 F H OCH3 CH3 CHZPh
26313 2 C1 CH3 F CH3 CHZPh
26413 2 H H H H CH z-
'F
26513 2 H H H CH3 CHz-
'F
26613 2 H H H CHzPh CHZ-
~F
26713 2 H H H H CHz~~-Cl
26813 2 H H H CH3 CHz~~--C1
26913 2 H H H CHZPh CH~ Cl
27013 2 H H H H CH~~F
27113 2 H H H H CHZ-~~
~
27213 2 H H H CH3 CH -
~-CH3
27313 2 F H H H CHZ-
F
27413 2 Cl H H H CH~
F
27513 2 CH3 H OH CH3 CHz~
F
-25-
f' .''' ~ ~t"g
~~~:~~
No.k n X1 XZ X3 R1 RZ
m
27613 2 F H C1 CHs CHI
27713 2 F H H H CH \F
~OCH3
27813 2 Cl H H H CHz-~-OCHs
27913 2 CHs H H CHs CH ~- C1
28013 2 F H C1 CHs CHz-~-Cl
28113 2 CHs OCHs H CHs H
28211 2 H H H H CHzPh
28311 2 H H H CHs CHZPh
28411 2 H H H CZHS CH2Ph
28522 2 H H H H CHZPh
28622 2 H H H CHs CHZPh
28722 2 H H H CHZPh CH2Ph
28822 2 F H Cl CHs CHZPh
28922 2 F H CHs CHs CHZPh
29022 2 CHs H H CHs CHZPh
29122 2 OCHs H H CHs CHZPh
29222 2 C1 H H CHs CHZPh
29322 2 OCHs C1 H CHs CHZPh
29422 2 F H OCHs CHs CHzPh
29522 2 C1 CHs F CHs CHZPh
29622 2 H H H H CH~
F
29722 2 H H H CHs CHz-
F
29822 2 H H H CH2Ph CHz~
F
-26-
~~~~9~~~
No. k m n X' XZ X3 gl gz
299222 H H H H H
300 1 2 2 H H H CH3 H
301 1 2 2 H H H H CZHS
-27-
X1
~(CHz)k C-(CHz)n~~N-Az
H1-N
i~~~ 2
(CHz)m is X
X
No. m n X1 Xz X3 gl gz
k
3021 2 2 H H H H CHZPh
3031 2 2 H H H CHs CHZPh
3041 2 2 H H H CzHS CHZPh
3051 2 2 H H H CHZPh CHZPh
3061 2 2 H H H COCHs CHzPh
3071 2 2 H H H COPh CHzPh
3081 2 2 H H CHs CHs CHZPh
3091 2 2 F H CHs CHs CHZPh
3101 2 2 H H F CHs CHzPh
31I1 2 2 H OCHsOCHs CHs CH2Ph
3121 2 2 OCHsH CHs CHs CHZPh
3131 2 2 H H C1 CHs CHZPh
3141 2 2 H Cl CHs CHs CHZPh
3151 2 2 H F OCHs CHs CHZPh
3161 2 2 Cl CHs F CHs CHZPh
3171 2 2 H H H CHs CHZCHZPh
3181 2 2 H H H CHs CHz
F
-28-
Vo. 1 m n X1 Xz X3 R' gz
319 1 2 2 H H H CHZPh CHz
F
320 1 2 2 H H H H CH Z~~-
F
321 1 2 2 H H H H CHz--~
F
322 1 2 2 H H H CHs CHZ-~-C1
323 1 2 2 H H H CHs CHz--~-OCH3
324 1 2 2 H H H CHs CHz .--~-CHs
325 1 2 2 H H CF H CH z~~
s
'F
326 1 2 2 H H C1 H CHz
,F
327 1 2 2 H H CHs CHs CHz-
'F
328 1 2 2 H F C1 CHs CHz
F
329 1 2 2 F H CHs H CHz-T'
F
330 1 2 2 Cl H CHs H CHzJ~'~~-pCHs
331 1 2 ? H H CHs CHs CHZ-~~--OCH3
332 1 2 2 H F Cl CHs CHz-~-OCHs
333 1 2 ~ H C1 CHs CHs CHz
~F
334 1 2 2 '~OzOCHs OCHs CHs CcHz~'
F
335 1 2 1 H H H H CHZPh
336 1 2 1 H H H CHs CHZPh
337 1 2 3 H H H H CHzPh
338 1 3 3 H H H CHs CHZPh
339 1 3 2 H H H H CHZPh
340 1 3 2 H H H GHs CHZPh
341 1 3 2 H H H CzHS CHZPh
-29-
2~~~~~
No. 1 m n X' XZ X3 K' RZ
342 1 3 2 H H H CHZPh CHZPh
343 1 3 2 H H H COCHs CHZPh
344 1 3 2 H H H COPh CH2Ph
345 1 3 2 H H CHs CHs CHZPh
346 1 3 2 H F CHs CHs CHZPh
347 1 3 2 F H CHs CHs CHZPh
348 1 3 2 H H OCHs CHs CHZPh
349 1 3 2 H H C1 CHs CHZPh
350 1 3 2 H C1 F CHs CHZPh
351 1 3 2 H CHs OCHs CHs CHZPh
352 1 3 2 C1 CHs F CHs CHZPh
353 1 3 2 H H H H CHZ-
F
354 1 3 2 H H H CHs CH~
F
355 1 3 2 H H H CHZPh CHZ-~
F
356 1 3 2 H H H H CHZ~~-C1
357 1 3 2 H H H CHI CHZ-~-C1
358 1 3 2 H H H CHZPh CHZ-~Cl
359 1 3 2 H H H H CHZ-~-F
360 1 3 2 H H H H CHZ
361 1 3 2 H H H CHs CHZ-~-Cg3
362 1 3 2 H H F H CH2
F
363 1 3 2 H H C1 H CH2
F
364 1 3 2 H H CHs CHs CHZ~
F
-30-
2~~~~~~~
lVo.1 m n X1 X2 X3 R' KZ
365 1 3 2 H H C1 CH3 CH~
366 1 3 2 H H OCH3 H CH F
~OCH3
367 1 3 2 SCH3 H CH3 H CHZ-~- OCH3
368 1 3 2 H CH3 CH3 CH3 CHI-~--C1
369 1 3 2 H H Cl CH3 CHI-~-C1
370 1 3 2 H OCH3 OCH3 CH3 CHZ-
F
371 1 2 2 H H H H H
372 1 2 2 H H H CH3 H
373 1 2 2 H H H CZHS H
374 1 2 2 H H H H CH3
375 1 2 2 H H H CH3 CH3
376 1 2 2 H H H CHZPh CH3
377 1 3 2 H H H CH3 H
378 1 3 2 H H CH3 CH3 H
379 1 3 2 H H F CH3 H
380 1 3 2 OCH3 H CH3 CH3 CH3
381 1 3 2 H H OCH3 CH3 CH3
-31-
~~j~~~
382 0
\C-(CHZ) z-~\N-CH2-
CH3N
383
CH3N
~C-(CHZ)z-~N-CH2
0
384 0
,a
C-(CH2) z-~N-CH2--
H
385
386
H
C-(CHZ)z ~N-CH2-
0
HN
C-(CH z ) z ~N-CH ~~--~
0
-32-
X~ 0
i_' CCHz) k,~ ~CHz) z ~N-A z
I~ V ~~~I I X z
~CH2)m X3
No. k m XI Xz X3 I~i Rz
387 0 5 H H H H CHzPh
388 0 5 H H H CH3 CHZPh
389 0 5 H H H CzHS CHZPh
390 0 5 H H H CHzPh CHZPh
391 0 5 H H H COCH3 CHZPh
392 0 5 H H H COPh CHZPh
393 0 5 H H H H H
394 0 5 H H H H CHz-
C1
395 0 5 CH3 H Cl CIi3 CH2-
CH3
396 0 ,~ F H OCH3 CH3 CHzPh
397 I 4 H H H H CHZPh
398 1 4 H H H CH3 CHZPh
399 1 4 H H H CZH~; GHZPh
400 I 4 H H H CHZPh CHaPh
401 1 4 H H H COCH3 CHZPh
402 I 4 H H H COPh CHZPh
403 I 4 CH3 H CH3 H CHz~-OCH3
404 1 4 Cl H H H CHzPh
405 1 4 CH3 H F CH3 CHz-
F
406 1 4 F H OCH3 CH3 CHZPh
407 2 3 H H H H CHZPh
-33--
2~~~~j~'~
~1 ~2
408 2 3 H H H CH3 CHZPh
409 2 3 H H H C2H5 CHZPh
410 2 3 H H H CHZPh CHZPh
411 2 3 H H H COCH3 CHZPh
412 2 3 H H H COPh CHZPh
413 2 3 CH3 H CH3 H CHZ-
F
414 2 3 C1 H H H CH2Ph
415 2 3 CH3 H F CH3 CHZ-~-
416 2 3 F H OCH3 CH3 CHZPh
417 3 2 H H H H CHZPh
418 3 2 H H H CH3 CHZPh
419 3 2 H H H CzHS CHZPh
420 3 2 H H H CHZPh CHZPh
421 3 2 H H H COCH3 CHZPh
422 3 2 H H H COPh CHZPh
423 3 2 CH3 H CH3 H CHz ~a
~F
424 3 2 C1 H H H CH2Ph
425 3 2 CH3 H F CH3 CHz
426 3 2 F H OCH3 CH3 CHZPh
427 0 6 H H H H CH2Ph
428 0 6 H H H CH3 CHZPh
429 0 6 H H H CZHS CHzPh
430 0 6 H H H CHZPh CHZPh
431 0 6 H H H COCH3 CHZPh
432 0 6 H H H COPh CH2Ph
433 0 6 H H C1 H CHz-
F
-34--
~0~~~
No. k m X1 Xz X3 K1 Rz
434 0 6 H H H H CHz~Cl
435 0 6 CH3 H F CH3 CHz
436 0 6 F H OCH3 CH3 CHZPh
437 1 5 H H H H CH2Ph
438 1 5 H H H CH3 CHZPh
439 1 5 H H H CZHS CHZPh
440 1 5 H H H CH2Ph CHZPh
441 1 5 H H H COCH3 CHZPh
442 1 5 H H H COPh CHZPh
443 1 5 H H C1 H CHz-~~
'NO z
444 1 5 H H CH3 H CHZPh
445 1 5 CH3 H F CH3 CHz
'SCH 3
446 1 5 F H OCH3 CH3 CHZPh
457 2 4 H H H H CHzPh
~
458 2 4 H H H CH3 CHZPh
459 2 4 H H H CZHs CHZPh
460 2 4 H H H CHZPh CHZPh
461 2 4 H H H COCH3 CHZPh
462 2 4 H H H COPh CHzPh
463 2 4 CH3 H CH3 H CHz
CN
464 2 4 Cl H H H CHZPh
465 2 4 CH3 H F CH3 CHZ--
'CF 3
466 2 4 F H OCH3 CH3 CHZPh
467 3 3 H H H H CHZPh
468 3 3 H H H CH3 CHZPh
469 3 3 H H H CzHS CHzPh
-35--
V A~
NO, k m ~(1 X2 X3 ~1 ~2
470 3 3 H H H CHZPh CHZPh
471 3 3 H H H COCH3 CHZPh
472 3 3 H H H COPh CHZPh
473 3 3 H H H H CHZ-
F F
474 3 3 H H H H CHZCHZ-
475 3 3 CH3 H F CH3 CH2
'F
476 3 3 F H OCH3 CH3 CHZPh
-36--
X1
~CCHz)k Xz
A~_N
CCHz)z~N-Hz
CCHz)m X3 0
No. k m X1 Xz X3 R1 Rz
477 0 5 H H H H CH2Ph
478 0 5 H H H CH3 CHZPh
479 0 5 H H H CZHS CHzPh
480 0 5 H H H CHZPh CHZPh
481 0 5 H H H COCH3 CHZPh
482 0 5 H H H COPh CHZPh
483 0 5 H H H H CHz-~~-C1
484 0 5 H H H H CH z ~v
485 0 5 CH3 H C1 CH3 CHz-~NHZ
'NHAc
486 0 5 F H 0CH3 CH3 CHZPh
-
487 1 4 H H H H CHZPh
488 1 4 H H H CH3 CHZPh
489 1 4 H H H CZHS CHZPh
490 1 4 H H H CHzPh CHzPh
501 1 4 H H H COCH3 CHzPh
502 1 4 H H H COPh CHZPh
503 1 4 CH3 H CH3 H CHz
SOzCH3
504 1 4 Cl H H H CHZPh
505 1 4 CH3 H F CH3 CHz
NHCOCF3
506 1 4 F H OCH3 CH3 CHZPh
507 0 6 H H H H CHzPh
-37--
No.k m X1 Xz X3 R1 gz
5080 6 H H H CH3 CHZPh
5090 6 H H H CzHS CHzPh
5100 6 H H H CHZPh CHZPh
5110 6 H H H COCH3 CHZPh
5120 6 H H H COPh CHZPh
5130 6 H H C1 H CHz-
C0CH3
5140 6 H H H H CHz
OH
5150 6 CH3 H F CH3 CHz
COPh
5160 6 F H OCH3 CH3 CHZPh
5171 5 H H H H CHzPh
5181 5 H H H CH3 CHZPh
5191 5 H H H C~HS CHZPh
5201 5 H H H CHzPh CHZPh
5211 5 H H H COCH3 CHzPh
5221 5 H H H COPh CHZPh
5231 5 H H Cl H CH z ~~y
CzHS
5241 5 H H CH3 H CH2Ph
5251 5 CH3 H F CH3 CHz-
~Ph
5261 5 F H OCH~ CH3 CHZPh
527~ 4 H H H H CHZPh
528'? 4- H H H CH3 CHZPh
5292 4 H H H CzHS CHZPh
5302 4 H H H CHzPh CHZPh
5312 4 H H H COCH3 CHZPh
5322 4 H H H COPh CHZPh
_3g_.
~~5~~~'~
No. k m X1 Xz X3 gl gz
533 2 4 CH3 H CH3 H CHz
COzH
534 2 4 C1 H H H CH2Ph
535 2 4 CH3 H F CH3 CHZ
CHzOH
536 2 4 F H OCH3 CH3 CHZPh
-39--
p ~N-Rz
(CHz)2
/ (CHz)k X1
R'-N
z
\ X
(CHz)m
s
X
No, k m Xz X3 R1 Rz
X1
537 1 1 H H H CHZPh
H
538 1 1 H H CHs CHZPh
H
539 1 1 H CHs H CHZPh
H
540 1 1 H C1 H CHZPh
H
541 1 1 H H COCHs CHZPh
H
542 1 1 H OCHs CHs CHZPh
H
543 1 1 H Cl H H
H
544 1 2 H Cl H CHZPh
H
545 1 2 H CHs H CHZPh
H
546 1 2 H F CHs CHZPh
CHs
547 1 2 H OCHs CzHS CH2Ph
F
548 1 2 H CHs H H
H
549 2 1 H C1 H CHZPh
H
550 2 1 H CHs H CHZPh
H
551 2 1 H F CHs CHZPh
CHs
552 2 1 H COCHs CzHS CHZPh
F
553 2 1 H G1 H H
H
554 1 3 H H H CHZPh
H
555 1 3 H CHs H CHZPh
H
556 1 3 H C1 H CHZPh
H
557 1 3 H H CHs CHzPh
H
558 2 2 H H H CHzPh
H
-40-
No.k m X' Xz X3 gl gz
5592 2 H H CHs H CHZPh
5602 2 H H Cl H CHZPh
5612 2 H H H CHs CHZPh
5623 1 H H H H CHZPh
5633 1 H H CHs H CHZPh
5643 1 H H C1 H CHZPh
5653 1 H H H CHs CHZPh
5660 5 H H H H CHZPh
5670 5 H H CHs H CHZPh
5680 5 H H Cl H CHZPh
5690 5 H H H CHs CHZPh
5701 4 H H H H CH2Ph
5711 4 H H GHs H CHZPh
5721 4 H H C.1 H CHZPh
5731 4 H H H CHs CHZPh
5742 3 H H H H CHZPh
5752 3 H H CHs H CHZPh
5762 3 H H Cl H CHZPh
5772 3 H H H CHs CHZPh
5783 2 H H H H CHZPh
5793 2 H H CHs H CHzPh
5803 2 H H Cl H CHZPh
5813 2 H H H CHs CHZPh
5820 6 H H H H CH2Ph
5830 6 H H CHs H CHZPh
~
5840 6 H H C1 H CHZPh
5850 6 H H H CHs CH2Ph
-41-
2~j~~~
No.k m X' XZ X3 y gz
5861 5 H H H H CHZPh
5871 5 H H CH3 H CHzPh
5881 5 H H C1 H CHZPh
5891 5 H H H CH3 CHZPh
5902 4 H H H H CHZPh
5912 4 H H CH3 H CHZPh
5922 4 H H C1 H CHZPh
5932 4 H H H CH3 CHZPh
5943 3 H H H H CHZPh
5953 3 H H CH3 H CHZPh
5963 3 H H C1 H CHZPh
5973 3 H H H CH3 CHZPh
-42-
X1
~(CHz)k~ Xz
R~_N
3
\(CHz)m X
0 ( CH z ) z ~~N-H z
No. k m X1 Xz X3 K' Rz
598 0 2 CHs H H H CH2Ph
599 0 2 C1 H H H CHZPh
600 0 2 H H H COCHs CH2Ph
601 0 2 OCHs H H CHs CH2Ph
602 0 2 CHs H H H H
603 0 3 H H H H CHzPh
604 0 3 H H H CHs CHZPh
605 0 3 Ci~3 H H CHs CHZPh
606 0 3 OCHs H H H CHZPh
607 0 3 H H H H H
608 0 5 Cl H H H CHZPh
609 0 5 H H H H CHZPh
610 0 5 CHs H H CHs CHZPh
611 0 5 OCHs H H H CH2Ph
612 0 5 H H H H H
613 1 4 H H - H H CHzPh
614 1 4 CHs H H H CHZPh
615 1 4 OCHs H H H CHZPh
616 1 4 H H H CHs CHZPh
617 0 6 H H H H CHZPh
618 0 6 CHs H H H CHZPh
619 0 6 C1 H H H CHZPh
-43-
c
k ~ xl x2 x3 AI AZ
620 0 6 H H H CH3 CHZPh
621 0 6 H H H H CHZPh
622 0 6 H H H CHZPh CHZPh
623 0 6 H H H CzHS CHZPh
624 0 6 H H H COPh CHZPh
625 0 6 H H H COCH3 CH2Ph
626 0 6 H H H COPh CHZPh
627 0 6 F H H CH3 CHZPh
628 0 6 F H CH3 H CHZPh
629 0 6 CH3 H H H H
630 1 5 H H H H CHZPh
631 1 5 CH3 H H H CHZPh
632 1 5 C1 H H H CHZPh
633 1 5 H H H CH3 CHZPh
634 '? 4 H H H H CHZPh
635 2 4 CH3 H H H CHZPh
636 2 4 OCH3 H H H CHZPh
637 2 4 H H H CH3 CHZPh
-44-
2i~~~~~
xl o
X (CHz)k (CHz)z~N-Az
\(CHz)m xz
x3
No. X k m X1 Xz X3 gz
638 0 0 2 H H H CHZPh
639 0 0 2 H H CHs CHZPh
640 0 0 2 H H H H
641 0 1 1 H H H CHZPh
642 0 1 1 H H CHs CHZPh
643 0 1 1 H H OCHs CHZPh
644 0 0 3 H H H CH2Ph
645 0 0 3 H H Cl CHZPh
646 0 0 3 H H OCHs CHZPh
647 0 1 2 H H CzHS CHZPh
648 0 1 2 H H H H
649 0 1 2 H CHs H CHz
650 0 2 1 H H H CHZPh
651 0 2 1 H H CHs CHzPh
652 0 2 1 H H CzHS CHzPh
653 0 0 4 H H H H
654 0 0 4 H H H CHZPh
655 0 0 4 H H CHs CHzPh
656 0 1 3 H H H CHZPh
657 0 1 3 H H CHs CHZPh
658 0 1 3 H H H CHs
659 0 2 2 H CHs H CHZPh
-45-
No. X k m X1 X2 X3 Rz
660 0 2 2 H H H CHZPh
661 0 2 2 H H OH CH2Ph
662 0 3 1 H H H CH2Ph
663 0 3 1 H H F CHZPh
664 0 3 1 H OH C1 CHZPh
665 0 0 5 H H CHs CHZPh
666 0 0 5 H H H CHZPh
667 0 1 4 H OCHs H CH2Ph
668 0 1 4 H H H CHZPh
669 0 2 3 H H H CHZPh
670 0 2 3 H H OH CHZPh
671 0 3 2 H CHs H CHZPh
672 0 3 2 H C1 CHs CHzPh
673 0 0 6 H H H CHZPh
674 0 0 6 H H H H
675 0 1 5 OH H H CHZPh
676 0 1 5 H H H CHZPh
677 0 2 4 H H CHs CHZPh
678 0 2 4 H H H CHZPh
679 0 3 3 H CHs H CHzPh
680 0 3 3 H H H CHZPh
681 S 0 2 H H H CHZPh
682 S 0 2 H H CHs CHzPh
683 5 0 2 H H H H
684 S 1 1 H H H CHzPh
685 S 1 1 H H CHs CHZPh
686 S 1 1 H H (~H3 CHzPh
-46-
2~j~~ ~"~
x k ~ xl x2 x3
687S 0 3 H H H CHzPh
688S 0 3 H H C1 CHZPh
689S 0 3 H H OCH3 CHzPh
690S 1 2 H H C2H5 CHZPh
691S 1 2 H H H H
692S 1 2 H CH3 H CH=CH-~
693S 2 1 H H H CHzPh
694S 2 1 H H CH3 CHZPh
695S 2 1 H H CzHS CHZPh
696S 0 4 H H H H
697S 0 4 H H H CH2Ph
698S 0 4 H H CH3 CHZPh
699S 1 3 H H H CHZPh
700S 1 3 H H CH3 CHZPh
701S 1 3 H H H CH3
702S 2 2 H CH3 H CHZPh
703S 2 ? H H H CHZPh
704S 2 2 H H OH CHZPh
705S 3 1 H H H CHZPh
706S 3 1 H H F CHZPh
707S 3 1 H OH C1 CHZPh
708S 0 5 H H CH3 CHZPh
709S 0 5 H H H CHZPh
710S 1 4 H OCH3 H CHZPh
711S 1 4 H H CHZPh
712S 2 3 H H H CHZPh
713S 2 3 H H OH CH2Ph
-47-
IVo,X k m X' X Z X 3 g z
714S 3 2 H CH3 H CHZPh
715S 3 2 H C1 CH3 CHZPh
716S 0 6 H H H CHZPh
717S 0 6 H H H H
718S 1 5 OH H H CHZPh
719S 1 5 H H H CHZPh
720S 2 4 H H CH3 CH2Ph
721S 2 4 H H H CHZPh
722S 3 3 H CH3 H CHZPh
723S 3 3 H H H CHZPh
-48-
e~ ~ '
X'
/(CHz)k Xz _
X ~ ~ (CHz) z~y,N-Az
~(CH )~n 3 0
X
No.X k m X1 Xz X3 gz
7240 0 2 H H H CH2Ph
7250 0 2 CH3 H H CHZPh
7260 0 2 H H H H
7270 0 3 H H H CHZPh
7280 0 3 OCH3 H CH3 CHZPh
7290 0 3 OH H OCH3 CHZPh
7300 0 4 H H H CHZPh
7310 0 4 Cl H H CH2Ph
7320 0 4 F H H CHZPh
7330 1 4 H H H CHZPh
7340 1 4 CH3 Cl H CHzPh
7350 0 5 H H H CHZPh
7360 0 5 H CH3 H CHZPh
7370 2 4 OH H H CHZPh
7380 2 4 H H H CHZPh
7390 1 5 H H H CH2Ph
7400 0 6 H H H CHZPh
741S 0 2 H H H CHZPh
742S 0 2 CH3 H H CHZPh
743S 0 2 H H H H
744S 0 3 H H H C~izPh
745S 0 3 OCH3 H CH3 CHZPh
-49-
2~~~~~~
lVo.X k m X' X X 3 g 2
2
746 S 0 3 OH H OCH3 CHZPh
747 S 0 4 H H: H CHZPh
748 S 0 4 C1 H H CHZPh
749 S 0 4 F H H CHZPh
750 S 1 4 H H: H CH2Ph
751 S 1 4 CH3 C1 H CHZPh
752 S 0 5 H H H CHZPh
753 S 0 5 H CH3 H CHZPh
754 S 2 4 OH H H CHZPh
755 S 2 4 H H H CHZPh
756 S 1 5 H H H CH2Ph
757 S 0 6 H H H CHZPh
-50-
2~~~~'~
p ~ CCHz) z~ .~-Rz
(CHz)k ~ X1
z
X (CH )m I X
X3
No. X k m X1 Xz X3 Iiz
758 0 0 2 H H H CHZPh
759 0 0 2 H H H CHzPh
760 0 1 1 H H H CHZPh
761 0 1 1 OCH3 H CH3 CH2Ph
762 0 0 3 H H H CH2Ph
763 0 0 3 H H Cl CHzPh
764 0 1 2 H H H CHZPh
765 0 1 2 H Cl CH3 CHZPh
766 0 2 1 H H H CHZPh
767 0 2 1 H CA's H CHZPh
768 0 0 :~ H H OH CHZPh
769 0 0 4 H H H CHZPh
770 0 1 3 H H H CHzPh
771 0 1 3 H H Cl CHZPh
712 0 2 2 H H H CHZPh
773 0 2 2 OCH3 H CH3 CHZPh
774 0 3 1 H H H CHZPh
775 0 3 1 H H C1 CHZPh
776 0 0 5 H H H CHZPh
777 0 0 5 H C1 CH3 CHZPh
778 0 1 4 H H H CHZPh
779 0 1 4 H CH3 H CHZPh
-51-
~~'~~P~ l
NO. X k III X1 XZ X3 R2
780 0 2 3 H H OH CHZPh
781 0 2 3 H H H CHZPh
782 0 3 2 H H H CHzPh
783 0 3 2 H H F CHZPh
784 0 0 6 H H H CHZPh
785 0 0 6 H C:1 CH3 CHZPh
786 0 1 ~ H H H CH2Ph
787 0 1 5 H Cli3H CHZPh
788 0 2 4 H H OH CHZPh
789 0 2 4 H H H CHZPh
790 0 3 3 H H H CHZPh
791 0 3 3 H H F CHZPh
792 S 0 3 H H H CHzPh
793 S 0 ~ H H H CHZPh
794 S 1 I H H H CHZPh
795 S 1 i OCH3 H CH3 CHZPh
796 S 0 3 H H H CHZPh
797 S 0 3 H H Cl CHZPh
798 S 1 ~ H H H CHZPh
799 S 1 2 H Cu' CH3 CHZPh
800 S 2 1 H H H CHZPh
801 S 2 1 H CH3 H CHZPh
802 S 0 4 H H OH CHZPh
803 S 0 4 H H H CHZPh
804 S 1 3 H H H CHZPh
805 s 1 3 H H C1 CHZPh
806 S 2 2 H H H CHZPh
-52-
No. X k m X1 XZ X3 RZ
807 S 2 2 OCH3 H CH3 CH2Ph
808 S 3 1 H H H CH2Ph
809 S 3 1 H H C1 CHZPh
810 S 0 5 H H H CHZPh
811 S 0 5 H C1 CH3 CHZPh
812 S 1 4 H H H CHZPh
813 S 1 4 H CH3 H CHZPh
814 S 2 3 H H OH CH2Ph
815 S 2 3 H H H CHZPh
816 S 3 2 H H H CHZPh
817 S 3 2 H H F CHZPh
818 S 0 6 H H H CHZPh
819 S 0 6 H C:L CH3 CHZPh
820 S 1 5 H H H CHZPh
82i S 1 5 H C1~3H CH2Ph
822 S 2 4 H H OH CHZPh
823 S 2 4 H H H CHZPh
824 S 3 3 H H H CHZPh
825 S 3 3 H H F CHZPh
-53-
2 ~~~~,~ ~
xl
~(CHz)k~ xz
3
X (CHz)m X
(CH2) 2
~J
x k m xl x2 x3
826 0 0 2 H H H CHZPh
827 0 0 2 CH3 H H CHZPh
828 0 0 3 H H H CHZPh
829 0 0 3 OCH3 H CH3 CHZPh
830 0 0 4 H H H CHZPh
831 0 0 4 Cl H H CHZPh
832 0 1 4 H H H CHZPh
833 0 1 4 OH Ci H CHZPh
834 0 0 5 H H H CHZPh
835 0 0 5 H CHs H CHZPh
836 0 2 4 OCH3 H OH CHZPh
837 0 2 4 H H H CHZPh
838 0 1 5 H H H CHZPh
839 0 0 6 H H H CHZPh
840 S 0 2 H H H CHZPh
841 S 0 2 OCH3 H H CHZPh
842 S 0 3 H H H CHZPh
843 S 0 3 OCH3 H CH3 CHZPh
844 S 0 4 H H H CHZPh
845 S 0 4 F H H CHZPh
846 S 1 4 H H H CHZPh
847 S 1 4 CH3 Cl. H CHZPh
-54-
No,X k m X1 X2 X3 gz
848S 0 5 H H H CH2Ph
849S 0 5 H CH3 H CHZPh
850S 2 4 H H H CHZPh
851S 2 4 CH3 H H CHZPh
852S 1 5 H H H CHZPh
853S 0 6 H H H CHZPh
- 55-
24205-912
The salt of compound (I) according to the present
invention is preferably a physiologically acceptable
acid addition salt. The salt mentioned above includes
salts with inorganic acids (e. g. hydrochloric acid,
phosphoric acid, hydrobromic acid, sulfuric acid) and
salts with organic acids (e. g. acetic acid, formic
acid, propionic acid, fumaric acid, malefic acid,
succinic acid, tartaric acid, citric acid, malic acid,
oxalic acid, benzoic acid, methanesulfonic acid,
benzenesulfonic acid)..
Furthermore, when the compound {I) according to
the present invention has an acidic group such as
COON, compound (I) may form a salt with an inorganic
base {e. g. sodium, patassium, calcium, magnesium,
ammonia) or an organic base (e. g. triethylamine).
The process for producing the compound (I) or its
salt of the invention is now described.
While the following description of the production
process applies not only to the production of compound
{I) but also to the production of its salt, they may be
referred to as the compound (I) below.
-56-
~v~~~~~~
24205-912
The compound (I) can be produced by reacting a
compound of the formula (II):
0
li ;-, CII)
Y-C-CCB?)it-';,:_~~;,N-Z
wherein Y is a halogen; n is as defined in formula (I);
Z is an amino-protecting group or a salt thereof with a
compound of the formula (III):
(CH2) k
(CHZ)m~, C III)
wherein each symbol is as defined in formula (I), or a
salt thereof and deprotecting the resulting compound of
the formula (IV):
r~1 0
ilCilZ) r ~~ /_-_'..
~C_ICHz)n.:; y_2 {IV)
~ (CHZ)m~
wherein each symbol is as defined hereinbefore or a
salt thereof.
Y is preferably chloro, bromo or iodo, and a more
preferable example of Y is chloro.
Z is preferably acetyl, benzoyl, formyl,
methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl or
benzyloxycarbonyl, and more preferable examples of Z
include acetyl and benzoyl.
Here, the compound of formula (II) or a salt
thereof can be prepared by processes which are
known per se or processes analogous thereto. For
example, it can be produced by the process described in
Chemical Pharmaceutical Bulletin, 34, 3747-3761 (1986).
The compound of formula (III) or a salt thereof
can be prepared by processes which are known ~e-r
-57-
24205-912
se or processes analogous thereto. For example, it can
be produced by the processes described in Journal of
the Organic Chemistry 34, 2235 (1969), Journal of the
Organic Chemistry 54, 5574 (1989), Tetrahedron letters
35, 3023 (1977), Bulletin of the Chemical Society of
Japan, 56 2300 (1983) and so on.
The salt of compound(I) or compound(IV) according to
the present invention is preferably a physiologically
acceptable acid addition salt. The salt mentioned
above includes salts with inorganic acids (e. g.
hydrochloric acid, phosphoric acid, hydrobromic acid,
sulfuric acid) and salts with organic acids (e. g.
acetic acid, formic acid, propionic acid, fumaric acid,
malefic acid, succinic acid, tartaric acid, citric acid,
malic acid, oxalic acid, benzoic acid, methanesulfonic
acid, benzenesulfonic acid).
The reaction between compound {II) or a salt thereof
(e.g. one of the salts mentioned for formula (I)) and
compound (III) or a salt thereof can be carried out as
follows, for instance. Thus, the compound {II) or a
salt thereof is allowed to react with the compound
(III) without using a solvent or in a solvent, where
necessary in the presence of an acid or the like. The
acid may be a Lewis acid (e. g. aluminum chloride, zinc
chloride, titanium chloride). The amount of such acid
is generally used at a ratio of 1 to 20 moles and
preferably 2 to 10 moles :relative to one mole of the
compound (II). The solvent may be any of the common
solvents used in chemical reactions provided it does not
interfere with the reaction. For example,
dichloromethane, dichloroethane, nitrobenzene, carbon
disulfide, etc. can be employed as the solvent. The
reaction temperature is generally about -30°C to 150°C
and preferably about 20°C to 100°C. The reaction time
is generally 0.5 to 72 hours. The amount of compound
(III) or a salt thereof is generally used at a ratio of
-58-
24205-912
1 to 20 moles and preferably about 1 to 5 moles
relative to one mole of the compound (II) or a salt
thereof.
The position of introduction of the group
S O
C- (CH2)n-~N-Z
of formula (II) into the compound of formula (III) in
the above reaction may be any positions of ring A which
can be substituted. For example it is predominantly
the 6-position when the skeletal structure of compound
(III) is 1,2,3,4-tetrahydroquinoline (where ring A is
unsubstituted). However, the compounds formed upon
introduction into other positions (5-, 7- and 8-
positions) may also be produced and isolated.
The compound (IV) or a salt thereof thus produced
can be isolated and purified by the conventional
procedures such as concentration, pH adjustment,
redistribution, solvent extraction, fractional
distillation, distillation, crystallization,
recrystallization, chromatography and so on. However,
the reaction mixture may be directly used as the
material to the next reaction stage.
The deprotection of the compound (IV} or a salt
thereof can be carried out by treating the compound
(IV) or a salt thereof with an acid or a base. Thus,
the compound of formula (IV) or a salt thereof is
maintained in an aqueous solution of mineral acid (e. g.
nitric acid, hydrochloric acid, hydrobromic acid, iodic
acid, sulfuric acid) or alkali metal hydroxide (e. g.
sodium hydroxide, potassium hydroxide, barium
hydroxide, lithium hydroxide) at 10° to 150°C,
preferably at 50° to 100°C. Such acid or
base is generally used at a ratio of 1 to 100
equivalents and preferably 1 to 40 equivalents relative
-59-
to the compound (IV) or a salt thereof. The strength
of the acid or base is generally about 1 to 10 N, and
preferably about 4 to 10 N. The reaction time, which
depends on the reaction temperature, is generally 1 to
24 hours and preferably about 2 to 10 hours.
The compound (I) {RZ=H) or a salt thereof thus
produced can be isolated and purified by the
conventional procedures such as concentration, pH
adjustment, redistribution, solvent extraction,
fractional distillation, distillation, crystallization,
recrystallization, chromatography and so on. However,
the reaction mixture may be directly used as the
material to the next reaction stage.
The compound (I) wherein RZ is a group other than
a hydrogen atom or a salt thereof can be produced by
reacting a compound (I) (RZ=H) or a salt thereof with a
compound of formula
R2~-Y~ (V)
wherein R~' is a hydrocarbon group which may be substi-
tuted; and Y' is a leaving group.
The leaving group Y' includes halogen {e. g.
chloro, bromo, iodo), C1_.6 alkylsulfonyloxy (e. g.
methanesulfonyloxy, ethanesulfonyloxy) and C6_lo
arylsulfonyloxy (e.g. benzenesulfonyloxy, p-
toluenesulfonyloxy).
The reaction between the compound (I) (RZ=H) or a
salt thereof and the compound (V) is conducted in a
solvent or without using a solvent, where necessary in
the presence of a base.
The base mentioned just above includes various
inorganic bases such as sodium carbonate, potassium
carbonate, lithium carbonate, sodium hydroxide,
potassium hydroxide, sodium methoxide, sodium ethoxide,
sodium hydride, etc. and various organic bases such as
pyridine, 4-dimethylaminopyridine, triethylamine and so
on. When a solvent is employed, the solvent includes
-60-
lower alcohols such as methanol, ethanol,propanol,
isopropyl alcohol, n-butanol, t-butanol, etc., ethers
such as dioxane, ether, tetrahydrofuran, etc., aromatic
hydrocarbons such as toluene, benzene, xylene, etc.,
amides such as dimethylformamide, dimethylacetamide,
hexamethylphosphonotriamide, etc., esters such as
ethyl acetate, butyl acetate, etc. which do not
interfere with the reaction. This reaction can be con-
ducted under cooling (about 0°C to 10°C), at room
temperature (about 10°C to 40°C) or under heating
(about 40°C to 120°C), and the reaction time is
generally 10 minutes to 48 hours and preferably 2 to 16
hours.
The preferred amount of compound (V) is generally
used at a ratio of 0.3 to 5.0 moles relative to one
mole of the compound (I) (RZ=H) or a salt thereof.
When a base is employed, the amount of the base is
generally used at a ratio of more than one mole and
preferably 1.1 to 5 moles relative to one mole of the
compound {I} {R'=H} or its salt.
If desired, this reaction may be hastened by con-
ducting it in the presence of sodium iodide, potassium
iodide, lithium iodide or the like. In such cases, the
amount of such iodide is generally used at a ratio of 1
to 5 moles and preferably 1.1 to 1.5 moles relative to
one mole of the compound (V}. Furthermore, the
compound (I) or a salt thereof can also be produced by
reacting a compound of the formula (VI):
/CCH~) k~
HN~ ~C-(CH2~ N-g2 Y
CCEz?~'~ ~ C I)
wherein k, m, n, ring A and R2 are as defined
hereinbefore or a salt thereof with a compound of the
formula (VII):
R1'-Y' ( VII )
-61-
2~~~~~r~
24205-912
wherein R1 is a hydrocarbon group which may be substi-
tuted or an acyl group which may be substituted; Y' is
as defined hereinbefore, under the same conditions as
those mentioned for the reaction between the compound
(I) (RZ=H) or a salt thereof and the compound (V).
Here, the compound of formula (VI) or a salt thereof
can be produced by the processes mentioned above and
can be also produced by hydrolyzing the compound
(I)(RZ~H) in which Ri is acyl or a salt thereof with an
acid or a base. This hydrolyzing reaction can be
conducted in the same manner as the deprotection of the
compound (IV) or a salt thereof.
The compound (I) can also be produced by other
known processes or processes analogous thereto (e. g.
the compound (I) can be prepared by reduction of the
compounds (IV), wherein Z is a carboxylic acid acyl,
protection and deprotection of functional groups of the
compound (IV) such as ketone may be necessary in the
process).
When the compound (I) thus obtained is a free
compound, it can be converted to its salt in the per se
conventional manner. When the product compound is a
salt, it can be converted to the free compound or a
different salt by the ,per se known procedure. The
compound (I) or its salt thus obtained can be isolated
and purified by the known procedures mentioned
hereinbefore.
The compound (I) or its salt according to the
present invention has effects on the central nervous
system of mammals, has high cholinesterase inhibitory
activity, and exhibits potent antiamnesic effects on
various amnesia-inducing factors in man and animals
(e. g. mice).
The compound (I) or its salt according to the
present invention features an excellent separation be-
tween effects on the central nervous system and those on
-62-
24205-912
the peripheral nervous system, as compared with
physostigmine and, at the antiamnesic dose level, does
not cause peripheral nervous system effects such as
spasm, salivation and diarrhea or, if it does, only
minimally. Moreover, it is characterized by a long
duration of effects as well as low toxicity and insures
a high efficacy when administered orally. The acute
toxicity of the compound (I) or its salt according to
the present invention is beyond 100 mg/kg.
Therefore, the compound (I) or a salt thereof of
the present invention is useful as an agent to improve
the brain function for mammalian animals including human
beings.
The compound (I) or a salt thereof of the present
invention may be used for such diseases as senile
dementia, Alzheimer's disease, Huntington's chorea,
hyperkinesia and mania, and may be used for the
prophylaxis or therapy of these diseases.
The compound (I) or a salt thereof according to
the present invention is generally formulated with a
pharmaceutically acceptable carrier or excipient and
can be administered orally or parenterally to man and
other mammalians .
Such pharmaceutical preparations may be those for
oral administration (e. g. powders, tablets, granules,
capsules, etc.) or for parenteral administration (e. g.
suppositories, injections). These preparations can be
manufactured by the per se known methods. While the
dosage depends on the type of disease and the symptom
to be controlled, the usual daily oral dosage per adult
human is about 0.01 to 100 mg, preferably 0.1 to 30 mg,
and more preferably 0.3 to 10 mg.
The following reference examples, working
examples, formulation examples and test examples are
intended to illustrate the present invention in further
detail and should by no means be construed as defining
-63-
~a~~~~~
the metes and bounds of the invention.
In the examples and reference examples, elution in
the procedure of column chromatography was carried out
under monitor by TLC {Thin-Layer Chromatography) unless
otherwise indicated. TLC monitoring was performed
using Merck Kieselgel 60 FZS4 (E. Merck) as the TLC
plate, the column elution solvent as the developer and
a UV detector for detection. As an adjunctive
detection procedure, the spot on the TLC plate was
sprayed with 48% HBr, heated to hydrolyze, sprayed with
ninhydrin reagent and reheated and the change to a
red - reddish purple color was regarded as positive
reaction. The fractions containing the object compound
were thus identified and pooled. Unless otherwise
specified, Merck Kieselgel 60 {70 to 230 mesh (E.
Merck)) was used as the silica gel for chromatography.
The term "ambient temperature" or "room
temperature" generally means about 5°C to 40°C and the
term "atmospheric pressure" means the neighborhood of
one atmosphere.
Unless otherwise specified, % denotes percentage
by weight.
Reference Example 1
1-Acetyl-6-[3-(1-acetylpiperidin-4-yl)-1-
oxopropyl]-1,2,3,4-tetrahydroquinoline
0
(1) In 300 ml of acetic acid was dissolved 33 g of
ethyl J3-(pyridin-4-yl)acrylate and catalytic
hydrogenation was carried out with platinum oxide as
the catalyst under atmospheric pressure at 70 to 80°C.
After 40 ml of acetic anhydride was added, the catalyst
-64-
was filtered off and the solvent was then distilled off
under reduced pressure. The residue was dissolved in
water and neutralized with potassium carbonate and the
reaction product was extracted with dichloromethane.
The extract was dried over anhydrous sodium sulfate and
the solvent was distilled off to give 44.8 g of an oily
compound.
{2) In 200 ml of methanol was dissolved 42.0 g of
the above oily compound followed by addition of a
solution of 12.7 g of potassium hydroxide in 20 ml of
water. The mixture was stirred at 50°C for 1.5 hours
and at room temperature for 12 hours. The reaction
mixture was neutralized with concentrated hydrochloric
acid and the solvent was distilled off. To the residue
was added methanol and the insoluble matter was
filtered off. The filtrate was concentrated and the
resulting crude crystals were collected by filtration
to give 27 g of 3-(1-acetylpiperidin-4-yl)propionic
acid {m. p. 201 to 206°C).
(3) To 20 ml of thionyl chloride was added 3.8 g of
3-(1-acetylpiperidin-4-yl)propionic acid in small
portions with ice-cooling and the mixture was stirred
for 5 minutes. The excess thionyl chloride was
distilled off and 15 g of carbon disulfide and 3.1 g of
1-acetyl-1,2,3,4-tetrahydroquinoline were added to the
solid residue followed by gradual addition of 10.7 g of
anhydrous aluminum chloride at room temperature. The
mixture was refluxed for 2 hours, after which it was
poured in ice-water and extracted with dichloromethane.
The extract was dried over anhydrous sodium sulfate and
the solvent was distilled off. The residue was
purified by chromatography (eluent: ethyl acetate-
methanol = 40:1 (v/v)) to give 1.4 g of a colorless
oil.
Elemental analysis, for C'1Hz$N203
Calcd.: C, 70.76; H, 7.92; N, 7.86
-65-
2U5~947
Found . C,, 70.08; H, 7.80; N, 7.64
Reference Example 2
1-Acetyl-6-[3-(1-acetylpiperidin-4-yl)-1-oxopro-
pyl]-1,2,3,4-tetrahydroquinoline (A) and 1-acetyl-7-[3-
(1-acetylpiperidin-~~-yl)-1-oxopropyl]-1,2,3,4-
tetrahydroquinoline (B)
(1) To 100 ml of thionyl crrloride was added 26 g of
3-(1-acetylpiperidi.n-4-yl)propionic acid, obtained in
Reference Example 1--(2), in small portions with ice-
cooling. The mixture was stirred for 5 minutes, after
which the excess th~~cnyl chloride was distilled off and
the solid residue was washed with diethyl ether to give
26 . 4 g of 3-( 1-acct rlF,ip~::~ i.c~i~i-4-yl jpropi«nyl chloride
as a pale yellow powder.
( 2 ) To a mixture of -~2. 5 <3 of 1-acetyl--1, 2, 3, 4-
tetrahydroquinoline and 30 rnl of carbon disulfide was
added 71 g of anhydrous aluminum chloride followed by
addition of 26.4 g of 3-(1-acetylpiperidin-4-
yl)propionyl chloride at room temperature. The mixture
was stirred at room temperature for 16 hours, after
which it was treated in the same manner as Reference
Example 1-(3) to give 25 g of a mixture of 1-acetyl-6-
[3-(1-acetylpiperidin-4-yl)-1-oxopropyl]-1,2,3,4-
tetrahydroquinoline {A) and 1-acetyl-7-[3-(1-
acetylpiperidin-4-yl)-1-oxopropyl]-1,2,3,4-tetra-
hydroquinoline (B) as a pale yellow oil.
Elemental analysis, for CZ1HZSNZOs
Calcci.: C, 70.76; H, 7.92; N, ?.86
Found . C, 70.81; H, 7.69; N, 7.83
' -66-
MC
Reference Example 3
1-Acetyl-5-[3-(1-acetylpiperidin-4-yl)-1-oxopro-
pyl]-2,3-dihydro-1H-indole
0
~lAc
Ac
Using 24 g of 1-acetyl-2,3-dihydro-1H-indole, the
procedure of Reference Example 2-(2) was followed to
give a solid. This solid was recrystallized from
dichloromethane-diethyl ether to give 26 g of colorless
crystals melting at 148 to 149°C.
Elemental analysis, for CZpH26N2~3
Calcd.: C, 70.15; H, 7.65; N, 8.18
Found . C, 69.97; H, 7.71; N, 7.98
Reference Example 4
1-Acetyl-8-[3-(1-acetylpiperidin-4-yl)-1-oxopro-
pyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (A) and 1-
acetyl-7-[3-(1-acetylpiperidin-4-yl)-1-oxopropyl]-
2,3,4,5-tetrahydro-1H-1-benzazepine (B)
/~~ a
~rAc
i ~Y
Ac ' N \V'~ NAc
(A) 4 Ac
~B~
Using 8.7 g of 1-acetyl-2,3,4,5-tetrahydro-1H-1-
benzazepine, the procedure of Reference Example 2-(2)
was followed to give a solid, which was then
recrystallized from dichloromethane-diethyl ether to
give 6.5 g of title compound A as colorless crystals
melting at 133 to 134°C.
Elemental analysis, for C22H30N2~3
Calcd.: C, 71.32; H, 8.16; N, 7.56
Found . C, 71.10; H, 8.21; N, 7.61
-67-
~~ ~~z ~~~1
24205-912
The recrystallization mother liquor was purified
by column chromatography (eluent: ethyl acetate:
methanol = 100:1) to recover 0.3 g of title compound B
as a pale yellow oil.
Elemental analysis, for C22H30N2~3
Calcd.: C, 71.32; H, 8.16; N, 7.56
Found . C, 71.13; H, 8.04; N, 7.43
Reference Example 5
8-[3-(1-Acetylpiperidin-4-yl)-1-oxopropyl]-
2,3,4,5-tetrahydro-1H-1-benzazepine
~Ac
t
Using 2.2 g of the compound obtained in Example
17, the procedure of Example 7-(1) was followed to give
2.15 g of colorless crystals melting at 86 to 88°C.
Elemental analysis, 'for C~oH~8N~0~
CalCd.: C, 73.14; H, 8.59; N, 8.53
Found . C, 72.91; H, 8.38; N, 8.47
Reference Example 6
5-[3-(1-Acetylpiperidin-4-yl)-1-oxopropyl]-1-
ethyl-2,3-dihydro-1H-indole
0
3 0 ~~'~ ~NAc
~Z$5
In 10 ml of ethanol were dissolved 0.8 g of 5-[3-
(1-acetylpiperidin-4-yl)-1-oxopropyl]-2,3-dihydro-1H-
indole, 2.1 g of ethyl iodide and 0.5 g of potassium
carbonate and the solution was refluxed for 24 hours.
-68-
2~~~°:~"~
The solid matter and the solvent were removed and the
residue was purified by column chromatography (eluent:
ethyl acetate: methanol = 20:1) to give 0.85 g of the
title compound as a pale yellow oil.
Elemental analysis, for CzoHz8N20z
Calcd.: C, 73.14; H, 8.59; N, 8.53
Found . C, 73.03; H, 8.54; N, 8.56
Reference Example 7
Using the compound obtained in Example 14-(1) or
Reference Example 5, the procedure of Reference Example
L 'was followed to give the compounds as oil as follows.
~(~~Z~k'
~NAc
CCH $ ) m.
Compound~~ m~ Ri Molecular Analysis
Calcd.
formula
(Found)
C H N
1 2 0 C3H7 CzlH3oNzCz73.65 8.83 8.18
(73.46 8.85 7.99)
2 2 O C4H9 CzzHszNzCz74.12 9.05 7.86
(74.03 9.02 7.61)
3 2 0 C5H11 Cz3H34Nz0z74.56 9.25 7.56
~
(74.51 9.09 7.45}
4 2 0 CHZCHZPh Cz6H3zNz0z77.19 7.97 6.93
(77.12 8.02 6.86)
5 0 4 CH3 C2lHsoN2~z73.65 8.83 8.18
(73.55 8.73 8.16)
6 0 4 CZHS Cz2H3zNz~2 9.05 7.86
74.12 8.96 7.75)
(74.01
-69-
Image
2~~~~ ~~l
24205-912
Reference Example 8
5-[3-(1-Acetylpiperidin-4-yl)-1-oxopropyl]-2,3-dihydro-
benzofuran
4
'oi '~G-~ ,N ~c
To 200 ml of 1,2-dichloroethane were added 9.65 g
(44 mmol) of 3-{1-acetylpiperidin-4-yl)propionic acid
chloride and 10.65 g (89 mmol) of 2,3-
dihydrobenzofuran. To the mixture was added 12.82 g
(96 mmol) of aluminum chloride in limited amounts, then
the mixture was stirred for 3 hours at room
temperature. The reaction mixture was poured into ice-
water, which was subjected to extraction with methylene
chloride. Organic layers were combined and washed
with water and dried over anhydrous sodium sulfate,
followed by distilling off the solvent. The res3~due
was purified by means of a silica gel coTusan
chromatography (ethyl acetate) to give 10.47 g (78~) of
5-[3-(1-acetylpiperidin-4-yl)-1-oxopropyl]-2,3-dihdyro-
benzofuran. Recrystallization from ittethlrlene
chloride-diethyl ether gave colorless needles, ~n.p. 93-
95°C..
Elemental Analysis for C,aH23N03:
Calcd.: C, 71.73; H, 7.69; N, 4.65
Found . C, 71.57; H, 7.77; N, 4.58
Reference Example 9
3-(1-Benzoylpiperidin-4-yl)propionic acid
4
C-'h ~~CHZCO~H
(1) In 100 ml of acetic acid was dissolved 12 g of
-71-
24205-912
ethyl j3-(pyridin-4-yl)acrylate and catalytic reduction
was carried out with 1 g of platinum oxide as the
catalyst under atmospheric pressure at 70-80°C. The
catalyst was filtered off and the solvent was distilled
off under reduced pressure, then the residue was
dissolved in 100 ml of dioxane. To the dioxane
solution was added 100 ml of an aqueous solution of 12
g of sodium hydrogen carbonate, and the mixture was
stirred for 20 minutes at room temperature. To the
resultant mixture was added dropwise 8 ml of benzoyl
chloride at room temperatures, and the mixture was
stirred for two hours. The reaction product was
extracted with dichloromethane. The extract was dried
over anhydrous sodium sulfate and the solvent was
distilled off to give 17.5 g of ethyl 3-(1-
benzoylpiperidin-4-yl) propionate as an pale yellow
oily product.
(2) Using 17 g of the compound obtained in (1), the
procedure of Example 1-{2) was followed to give 15 g of
, the the above-titled compound as colorless crystals,
m.p. 153-155°C.
Elemental Analysis for C~SH19N03:
Calcd.: C, 68.94; H, 7.33; N, 5.36
Found . C, 68.71; H, 7.44; N, 5.20
Reference Example 10
3-Methoxycarbonyl-2,3,4,5-tetrahydro-1H-3-benzazepine
I ~-'CQa~fe
In 150 ml of water was dissolved 4.13 g (0.10
mol.) of sodium hydroxide. To the solution was added
15.27 g (10.4 mmol.) of 2,3,4,5-tetrahydro-1H-3-
benzazepine. The reaction mixture was cooled with ice,
and then was added dropwise 7.9 ml (0.10 mol.) of
-72-
24205-912
methyl chloroformate. The mixture was stirred for 2.5
hours at room temperature, then extracted with
dichloromethane. The extract was dried over anhydrous
sodium sulfate and the solvent was distilled off to
leave 20.46 g (96$) of 3-methoxycarbonyl-
2,3,4,5-tetrahydro-1H-3-benzazepine as colorless
crystals. Recrystallization from diethyl ether - n-
hexane gave colorless needles, m.p. 53-54°C.
Elemental Analysis for CLZHisN~2:
Calcd.: C, 70.22; H, 7.37; N, 6.82
Found . C, 70.02; H, 7.41; N, 6.68
Reference Example 11.
3-Methoxycarbonyl-7-[3-(1-benzoylpiperidin-4-yl)-1-
oxopropyl]-2,3,4,5-tetrahydro-1H-3-benzazepine
0
Ye42C-N~r
Under ice-cooling, 1.5 ml of thionyl chloride was
added dropwise to 1.08 g (4.1 mmol.) of 3-(1-benzoyl-
piperidin-4-yl)propionic acid obtained in Reference
Example 9. The mixture was stirred for 40 minutes at 0°
C, then thionyl chloride was distilled off. The
residue was dissolved in 20 ml of 1,2-dichloroethane,
to which was added 0.81 g (3.9 mmol.) of 3-
methoxycarbonyl-2,3,4,5-tetrahydro-1H-3-benzazepine
obtained in Reference Example 10. To the mixture was
added 1.75 g (13.1 mmol.) of aluminum chloride in small
portions. The mixture was stirred for one hour at room
temperature, then the reaction mixture was poured into
ice-water and extracted with dichloromethane. The organic
layers were combined and washed with water once, then
dried over anhydrous sodium sulfate, followed by
distilling off the solvent. Purification by means of a
-73-
24205-912
silica gel column chromatography gave 1.46 g (83~) of
3-methoxycarbonyl-7-[3-(1-benzoylpiperidin-4-yl)-1-
oxopropyl]-2,3,4,5-tetrahydro-1H-3-benzazepine.
Recrystallization from ethyl acetate - n-hexane gave
colorless needles, m,p. 120-123°C.
Elemental Analysis for CZ~H32N2O4:
Calcd.: C, 72.30; H, 7.19; N, 6.25
Found . C, 71.99; H, 7.22; N, 6.12
Reference Example 12
6-[3-(1-Acetylpiperidin-4-yl)-1-oxopropyl]-3,4-
dihydro-2H-1-benzothiopyran
v
NAc
To a mixture of 3,4-dihydro-2H-1-benzothiopyran
(1.5g) and 3-(1-acetylpiperidin-4-yl)propionyl chloride
(2.18g) in 1,2-dichloroethane (20m1) was added aluminum
chloride (3.2g) portionwise at 10-15°C. The mixture
was stirred at room temperature for 2 hours then
refluxed for additional 2 hours, and poured into ice-
water. The mixture was extracted with dichloromethane,
washed with water, dried over anhydrous sodium sulfate.
The solvent was distilled off. The residue was
purified by silica gel column chromatography
(developing solvent: ethyl acetate) to obtain 2.7g of
the title compound as a pale yellow oil.
Elemental analysis, for C19H2sN~zS
Calcd.: C, 68.85; H, 7.60; N, 4.23
Found . C, 68.66; H, 7.62; N. 4.13
- 74 -
2~~'~~'~ r
24205-912
Reference Example 13
2-Acetyl-8-chloro-1,2,3,4-tetrahydroisoquinoline
1
A -N ~
C
./
To a mixture of 28.6 g of 8-chloro-1,2,3,4-tetra-
hydroisoquinoline hydrochloride in 140 ml of dichloromethane was
added 140 ml of 1N aqueous NaOH solution and 17.6 g of NaHC03. To
the solution was added dropwise 14.5 ml of acetic anhydride at
5°C. The mixture was stirred at room temperature for 1 hour.
The organic layer was separated and the aqueous layer was extrac-
ted with dichloromethane. The combined organic extracts were
washed with water, dried over anhydrous sodium sulfate. The sol-
vent was distilled off to give 29.1 g of the title compound as a
pale red oil.
Elemental analysis, for C11H12~1N0:
Calcd.: C, 63.01; H, 5.77; N, 6.68.
Found . C, 62.82; H, 5.86; N, 6.56.
Reference Example 14
2-Acetyl-5-[3-(1-benzoylpiperidin-4-yl)-1-oxopropyl]-
8-chloro-1,2,3,4-tetrahydroisoquinoline
C1
A
C
N
O
O / CH2CH2 N - C
- 74a -
24205-912
Using 21.0 g of the compound obtained in Reference
Example 13, the procedure of Reference Example 11 was followed
to give 9.2 g of the title compound as a pale yellow oil.
Elemental analysis, for C28H29C1N203:
Calcd.: C, 68.94; H, 6.45; N, 6.18.
Found . C, 68.83; H, 6.52; N, 6.04.
Example 1
6-[1-Oxo-3-(piperidin-4-yl)propyl]-1,2,3,4-tetra-
hydroquinoline
- 74b -
2~~~~~~'~
H
N NH
C~ ..~. .
r
A mixture of 1.3 g of 1-acetyl-6-[3-(1-acetyl-
piperidin-4-yl)-1-oxopropyl]-1,2,3,4-
tetrahydroquinoline obtained in Reference Example 1 and
20 ml of concentrated hydrochloric acid was refluxed
for 16 hours. The reaction mixture was then
concentrated and the residue was dissolved in water.
This solution was washed with ether and the aqueous
layer was adjusted to pH about 10 with 10~ sodium
hydroxide solution and extracted with dichloromethane.
The extract was dried over anhydrous sodium sulfate and
the solvent was distilled off under reduced pressure to
give 0.9 g of a colorless oil.
Elemental analysis, for C1~H~4N~0
Calcd.: C, 74.'6; H, 8.88; N, 10.29
Found . C, 74.'87; H, 8.68; N. 10.30
Example 2
5-[1-Oxo-3-[1-(phenylmethyl)piperidin-4-
yl]propyl;-1,2,3,4-tetrahydroquinoline dihydrochloride
H
,N
~ 2H~1
i
To a mixture of 1.3 g of 6-[1-oxo-3-(piperidin-4-
yl)propyl]-1,2,3,4-tetrahydroquinoline, 0.9 g of
potassium carbonate and 10 ml of ethanol was added
dropwise 2 ml of an ethanolic solution of 0.74 g of
benzyl bromide with ice-cooling. The mixture was
stirred at room temperature for 2 hours and the solid
-75-
24205-912
matter and the solvent were removed. The residue was
subjected to column chromatography (eluent; ethyl
acetate: methanol = 20:1 (v/v)) and the eluate
containing the desired campound was distilled to remove
the solvent. The residue was treated with 2.4 ml of 4N
methanolic hydrochloride to give a solid. This solid
was recrystallized from methanol-ether to give 1.55 g
of a colorless powder melting at 110 to 125°C (decomp.)
Elemental analysis, for C24H3oNZO~2HC1
Calcd.: C, 66.20; H, 7.41; N, 6.43
Found . C, 66.00; H, 7.35; N, 6.22
Example 3
1-(Phenylmethyl)-6-[3-[1-(phenylmethyl)piperidin-
4-yl]-1-oxopropyl]-1,2,3,4-tetrahydroquinoline
dihydrochloride
-2HCI
U
To 5 ml of a solution of 0.5 g of 6-[1-oxo-3-[1-
(phenylmethyl)piperidin-4-yl]propyl]-1,2,3,4-
tetrahydroquinoline (free base) obtained in Example 2
in N,N-dimethylformamide was gradually added 40 mg of
sodium hydride (oil-free) and the mixture was stirred
at room temperature for 1 hour. To this solution was
added dropwise 0.22 g of benzyl bromide with ice-
cooling and the mixture was stirred at room temperature
for 6 hours. The reaction mixture was then treated as
in Example 2 and the residue was purified by column
chromatography (eluent; ethyl acetate: methanol = 20:1
(v/v)). The eluate containing the desired compound was
distilled under reduced pressure to remove the solvent
-76-
~~~~~'~~r~
24205-912
and the resulting oil was treated with 0.7 ml of 4N-
methanolic hydrochloric acid to give a solid. This
solid was recrystallized from ethanol-ether to give
0.28 g of colorless crystals melting at 112 to 117°C
(decomp.).
Elemental analysis, for C31H36N2~~2HC1
Calcd.: C, 70.85; H, 7.29; N, 5.33
Found . C, 70.81; H, 7.12; N, 5.18
Example 4
1-Methyl-6-[3-[1-(phenylmethyl)piperidin-4-yl]-1-
oxopropyl]-1,2,3,4-tetrahydroquinoline dihydrochloride
CH$
2HC I
U
To 3 ml of a solution of 0.2 g of 6-[3-[1-(phenyl-
methyl)piperidin-4-yl]-1-oxopropyl]-1,2,3,4-tetrahydro-
quinoline dihydrochloride obtained in Example 2 in
N,N-dimethylformamide was gradually added 37 mg of
sodium hydride (oil-free). The mixture was stirred at
room temperature for 1 hour, after which 62 mg of
methyl iodide was added. The mixture was stirred at
room temperature for 6 hours, at the end of which time
15 mg of sodium hydride (oil-fee) and 40 ml of ethyl
chlorocarbonate were added in that-order. The mixture
was stirred for 1 hour and then poured in ice-water and
extracted with dichloromethane. The extract was dried
over anhydrous sodium sulfate and the solvent was
distilled off under reduced pressure. The residue was
subjected to column chromatography (eluent; ethyl
acetate: methanol = 20:1 (v/v)) and the eluate
containing the desired compound was distilled under
-77_
'~ ~ ~ a va r_~
24205-912
reduced pressure to remove the solvent. The resulting
oil was treated with 0.23 ml of 4N-methanolic
hydrochloric acid to give 0.1 g of an amorphous powder.
Elemental analysis, for CZSHszN20~2HC1
Calcd.: C, 66.81; H, 7.62; N, 6.23
Found . C, 66.83; H, 7.55; N, 6.09
Example 5
6-[1-Oxo-3-(piperidin-4-yl)propyl]-1,2,3,4-tetra-
hydroquinoline (A) and 7-[1-oxo-3-(piperidin-4-yl)pro-
pyl]-1,2,3,4-tetrahydroquinoline (B)
H
~ ..
(A) ~ (B)
Using 23 g of the compound obtained in Reference
Example 2, the procedure of Example 1 was followed to
20~ give 16.9 g of a mixture of 6-[1-oxo-3-(piperidin-4-
yl)propyl]-1,2,3,4-tetrahydroquinoline (A) and 7-[1-
oxo-3-(piperidin-4-yl)-propyl]-1,2,3,4-tetrahydroquin-
oline (B) as a pale yellow oil.
Elemental analysis, for C1~H~~N20
Calcd.: C, 74.96; H, 7.88; N, 10.29
Found . C, 74.69; H, 8.90; N, 10.22
Example 6
6-[1-Oxo-3-[1-(phenylmethyl)piperidin-4-
yl]propyl]-1,2,3,4-tetrahydroquinoline fumarate (A) and
7-[1-Oxo-3-[1-(phenylmethyl)piperidin-4-yl]propyl]-
1,2,3,4-tetrahydroquinoline fumarate (B)
_78_
~~~~~~rl
h :y . ~' CA7
J
$OzC
COZH
N~ ,. ~ ~ B )
Using 1.8 g of the compound obtained in Example 5,
the procedure of Example 2 was followed to give 1.82 g
of the free base of the title compound mixture A and B.
The first crop of crystals (0.65 g) from a solution of
this mixture in diethyl ether, i.e. 7-[1-oxo-3-[1-
(phenylmethyl)piperidin-4-yl]propyl]-1,2,3,4-
tetrahydroquinoline (m. p. 132-135°c), was treated with
an equivalent of fumaric acid to give 0.69 g of the
title fumarate (B) as colorless crystals melting at 175
to 177°C (decomp.).
Elemental analysis, for C~4H3oN,0~C4H404
Calcd.: C, 70.27; H, 7.16; N, 5.85
Found . C, 70.01; H, 6.97; N, 5.98
The mother liquor of said diethyl ether solution
was also concentrated to recover 0.7 g of 6-[1-oxo-3-
[I-(phenylmethyl)piperidin-4-yl]propyl]-1,2,3,4-tetra-
hydroquinoline as crystals (m. p. 126 to 129°C). This
crop of crystals was treated with an equivalent of
fumaric acid to give 0.78 g of the title fumarate (A)
as colorless crystals melting at 138 to 142°C (decomp.)
Elemental analysis, for C24H30N2~~C4H4~4
Calcd.: C, 70.27; H, 7.16; N, 5.85
Found . C, 70.13; H, 7.13; N, 5.77
Example 7
_79_
~~~~~'l~~'~
24205-912
1-Methyl-6-[1-oxo-3-(piperidin-4-yl)propyl]-
1,2,3,4-tetrahydroquinoline (A) and 1-methyl-7-[1-oxo-
3-(piperidin-4-yl)propyl]-1,2,3,4-tetrahydroquinoline
(B)
OA3 ~$3
11
(1) To 40 ml of a solution of 14.2 g of the compound
obtainea in Example 5 in dichloromethane was added
dropwise 10 ml of a solution of 5.1 g of acetic
anhydride in dichloromethane with ice-cooling. The
mixture was then stirred at room temperature for 10
minutes, after which. it was washed with 10~ sodium
hydroxide solution and dried over anhydrous sodium
sulfate. Finally the solvent was distilled off to give
14.9 g of a mixture of 6-[1-oxo-3-(1-acetylpiperidin-4-
yl)propyl]-1,2,3,4-tetrahydroquinoline and 7-[1-oxo-3-
(1-acetylpiperidin-4-yl)propyl]-1,2,3,4-
tetrahydroquinoline as a colorless oil.
(2) A mixture of 7.1 g of the oil obtained in (1)
and 1.6 g of trimethyl phosphate was heated at 190°C
for 2 hours. After cooling to room temperature, 20 ml
of dichloromethane as well as aqueous sodium hydroxide
solution (NaOH/HZO = 1.74 g/11 ml) was added and the
mixture was refluxed for 2 hours. The dichloromethane
layer was washed with water and dried over anhydrous
sodium sulfate and the solvent was distilled off. The
residue was purified by column chromatography (eluent;
ethyl acetate: methanol = 30:1) to give 5.5 g of a
mixture of 6-[3-(1-acetylpiperidin-4-yl)-1-oxopropyl]-
1-methyl-1,2,3,4-tetrahydroquinoline and 7-[3-(1-
acetylpiperidin-4-yl)-1-oxopropyl]-1-methyl-1,2,3,4-
tetrahydroquinoline as a pale yellow oil.
(3) Using 3.9 g of the oil obtained in (2), the pro-
_g0_
cedure of Example 1 was followed to give 3.2 g of a
mixture of the title compounds as a pale yellow oil.
Elemental analysis, for CigH26Nz0
Calcd.: C, 75.48; H, 9.15; N, 9.78
Found . C, 75.21; H, 9.06; N, 9.82
Example 8
1-Methyl-6-[1-oxo-3-[1-(phenylmethyl)piperidin-4-
yl]-propyl]-1,2,3,4-tetrahydroquinoline fumarate (A)
and 1-methyl-7-[1-oxo-3-[1-(phenylmethyl)piperidin-4-
yl]propyl]-1,2,3,4-tetrahydroquinoline fumarate (B)
Oy
CHs i
d ~°'
CO~H
. CB)
Ii0 ~C
Using 3.1 g of the compound obtained in Example 7,
the procedure of Example 2 was followed to give 3.8 g
of the free base of the mixture of title compounds A
and B. This mixture was purified by chromatography
(eluent; ethyl acetate: methanol = 50:1) to give 1.6 g
of 1-methyl-6-[loxo-3-[1-(phenylmethyl)piperidin-4-
yl]propyl]-1,2,3,4-tetrahydroquinoline (colorless oil)
and 1.7 g of lmethyl-7-[1-oxo-3-[1-
(phenylmethyl)piperidin-4-yl]propyl]-1,2,3,4-
tetrahydroquinoline (colorless oil).
Then, 1.6 g of 1-methyl-6-[1-oxo-3-[1-(phenylme-
thyl)piperidin-4-yl]propyl]-1,2,3,4-tetrahydroquinoline
was treated with an equivalent of fumaric acid to give
1.7 g of the title fumarate (A) as colorless crystals
melting at 170 to 172°C (decomp.)
-81-
,tr ~ b
~~~~~'v'~
24205-912
Elemental analysis, for CZSH32Nz0~CaHa04
Calcd.: C, 70.71; H, 7.37; N, 5.69
Found C, 70.61; H, 7.24; N, 5.63
On the other hand, 1.7 g of 1-methyl-7-[1-oxo-3-
[1-(phenylmethyl)piperidin-4-yl]propyl]-1,2,3,4-tetra-
hydroquinoline was treated with an equivalent of
fumaric acid to give 1.65g of the title fumarate (B) as
colorless crystals melting at 143 to 144°C (decomp.)
Elemental analysis, for CZSH3zN20~C~H~04
Calcd.: C, 70.71; H, 7.37; N, 5.69
Found . C, 70.54; H, 7.09; N, 5.77
Example 9
1-(Phenylmethyl)-6-[1-oxo-3-(piperidin-4-yl)pro-
pyl]-1,2,3,4-tetrahydroquinoline (A) and 1-(phenylme-
thyl)-7-[1-oxo-3-(piperidin-4-yl)propyl]-1,2,3,4-tetra-
hydroquinoline (B)
2 0 '~,~ ~~'Y H
c a)
(1) To a mixture of 5.2 g of the compound obtained
in Example 7-(1), 3.0 g of potassium carbonate and 30
ml of ethanol was added dropwise 5 ml of an ethanolic
solution of 2.7 g of benzyl bromide with ice-cooling.
The mixture was stirred at room temperature for 2 hours
and the solid matter and the solvent were removed. The
residue was subjected to chromatography (eluent; ethyl
acetate: methanol = 20:1 (v/v)) to give 3.2 g of 7-[3-
(1-acetylpiperidin-4-yl)-1-oxopropyl]-1-(phenylmethyl)-
1,2,3,4tetrahydroquinoline (a colorless oil) and 1.8 g
of 6-[3-(1-acetylpiperidin-4-yl}-1-oxopropyl]-
-82-
2~~~~~~ ~~
1,2,3,4-tetrahydroquinoline.
(2) A mixture of I.8 g of 6-[3-{1-acetylpiperidin-4-
yl)-1-oxopropyl]-1,2,3,4-tetrahydroquinoline recovered
in (1), 1.03 g of potassium carbonate, 1.96 g of benzyl
bromide and 20 ml of ethanol was refluxed for 5 hours
and the solid matter and the solvent were removed. The
residue was subjected to chromatography (eluent; ethyl
acetate: methanol = 20:1) to give 2.1 g of 6-[3-(1-
acetylpiperidin-4-yl.)-1-oxopropyl]-1-(phenylmethyl)-
1,2,3,4-tetrahydroquinoline as a colorless oil.
{3) Using 3.15 g of 7-[3-(1-acetylpiperidin-4-yl)-1-
oxopropyl]-1-(phenylmethyl)-1,2,3,4-tetrahydroquinoline
obtained in (1), the procedure of Example 1 was
followed to give 2.8 g of 1-(phenylmethyl)-7-[1-oxo-3-
(piperidin-4-yl)propyl]-1,2,3,4-tetrahydroquinoline (B)
as a pale yellow oil..
Elemental analysis, for Cz4HsoNzO
Calcd.: C, 79.52; H, 8.34; N, 7.73
Found . C, 79.2'.8; H, 8.21; N, 7.59
(4) Using 1.9 g of 6-[3-(1-acetylpiperidin-4-yl)-1-
oxopropyl]-1-(phenyl.met:~yl)-1,2,3,4-tetrahydroquinoline
obtained in (2), the procedure of Example 1 was
followed to give 1.63 g of 1-(phenylmethyl)-6-[1-oxo-3-
(piperidin-4-yl)propyl]-:L,2,3,4-tetrahydroquinoline (A)
as a pale yellow oil..
Elemental analysis, for Cz4H3oNz~
Calcd.: C, 79.52; H, 8.34; N, 7.73
Found . C, 79.43; H, 8.16; N, 7.48
Example 10
1-(Phenylmethyl)-6-[1-oxo-3-[1-
(phenylmethyl)piperi.din-4-yl]propyl]-1,2,3,4-
tetrahydroquinoline fumarate
-83-
2~~~~~7
cazH
Adz
Using 1.5 g of the compound obtained in Example 9-
(4), the procedure of Example 2 was followed to give
1.6 g of 1-(phenylmethyl)-6-[1-oxo-3-[1-
(phenylmethyl)piperidin-4-yl]propyl]-1,2,3,4-
tetrahydroquinoline (free base) as a colorless oil.
This oil (1.6 g) was treated with an equivalent of
fumaric acid to give 1.7 g of the title fumarate as
colorless crystals melting at 178 to 181°C (decomp.)
Elemental analysis, for C31H36N2~~C4H4~4
Calcd.: C, 73.92; H, 7.09; N, 4.93
Found . C,. 73.64; H, 7.22; N, 4.84
Example 11
1-(Phenylmethyl)-7-[1-oxo-3-[1-(phenylmethyl)pipe-
ridin-4-yl]propyl]-1,2,3,4-tetrahydroquinoline fumarate
CO~H
ga
Using 2.75 g of the compound obtained in Example
9-(3), the procedure of Example 2 was followed to give
2.95 g of 1-(phenylmethyl)-7-[1-oxo-3-[1-
(phenylmethyl)piperidin-4-yl]propyl]-1,2,3,4-
tetrahydroquinoline (free base) as a colorless oil.
This oil (2.95 g) was treated with an equivalent of
fumaric acid to give 3.1 g of the title fumarate as
-84-
colorless crystals melting at 180 to 182°C (decomp.).
Elemental analysis, for C31H36N2~~C4H4~4
Calcd.: C, 73.92; H, 7.09; N, 4.93
Found . C, 73.72; H, 7.02; N, 4.86
Example 12
2,3-Dihydro-5-[1-oxo-3-(piperidin-4-yl)propyl]-1H-
indole
W
H
Using 10 g of the compound obtained in Reference
Example 3, the procedure of Example 1 was followed and
the resulting solid product was recrystallized from
dichloromethane - diethyl ether to give 7.08 g of pale
yellow crystals melting at 137 to 139°C.
Elemental analysis, for C:6HZZN20
Calcd.: C, 74.38; H, 8.58; N, 10.84
Found . C, 74.11; H, 8.75; N, 10.67
Example 13
2,3-Dihydro-5-[1-oxo-3-[1-(phenylmethyl)piperidin-
4-yl]propyl]-1H-indole fumarate
. 0H
g HO yC
Using 2 g of the compound obtained in Example 12,
the procedure of Example 2 was followed to give 2.3 g
of the free base of the title compound as colorless
crystals melting at 81 to 82°C. The crystals (2.3 g)
were then treated with an equivalent of fumaric acid to
give 2.6 g of the title fumarate as colorless crystals
-85-
melting at 150 to 153°C (decomp.).
Elemental analysis, for C23H28Nz0~C4H404
Calcd..: C, 69.81; H, 6.94; N, 6.03
Found. . C, 69.68; H, 6.71; N, 5.93
Example 14
2,3-Dihydro-1-methyl-5-[1-oxo-3-[1-(phenylmethyl)-
piperidin-4-yl]propyl]-1H-indole fumarate
to a2H
CH3 HOZ
(1) Using 3 g of the compound obtained in Example
12, the procedure of Example 7-(1) was followed to give
3.1 g of 5-[3-(1-acetylpiperidin-4-yl)-1-oxopropyl]-
2,3-dihydro-1H-indole as colorless crystals melting at
145 to 146°C.
Elemental analysis, for C18H24NZOz
Calcd.: C, 71.97; H, 8.05; N, 9.33
Found . C, 71.92; H, 7.94; N, 9.11
(2) Using 1.5 g of the compound prepared in (1), the
procedure of Example 7-{2) was followed to give 1.25 g
of 5-[3-(1-acetylpiperidin-4-yl}-1-oxopropyl]-2,3-
dihydro-1-methyl-1H-indole as a colorless oil.
(3) Using 1.0 g of the compound obtained in (2), the
procedure of Example 1 was followed to give 0.83 g of
2,3-dihydro-1-methyl-5-[1-oxo-3-(piperidin-4-yl)propyl-
lHindole as a pale yellow oil.
Elemental analysis, for Cl~Hz4N20
Calcd.: C, 74.96; H, 8.88; N, 10.29
Found . C, 74.69; H, 8.79; N, 10.33
(4) Using 0.53 g of the compound obtained in (3),
the procedure of Example 2 was followed to give 0.51 g
of the free base of the title compound as a colorless
oil. This oil (0.51 g) was treated with an equivalent
-86-
~~~~~'i~)
~' ~.x a
24205-912
of fumaric acid to give 0.57 g of the title fumarate as
colorless crystals melting at 147 to 151°C (decomp.).
Elemental analysis, for Cz4H3oNz0~C4H404
Calcd.: C, 70.27; H, 7.16; N, 5.85
Found . C, 70.06; H, 7.09; N, 5.80
15
Example 15
2,3-Dihydro-5-[1-oxo-3-[1-(phenylmethyl)piperidin-
4-yl]propyl]-1-{phenylmethyl)-1H-indole fumarate
P
z~
1 v
HO ~C
{1) Using 0.65 g of the compound obtained in Example
14-(1), the procedure of Example 9-(2) was followed to
give 0.77 g of 5-[3-(1-acetylpiperidin-4-yl)-1-oxopro-
pyl]-2,3-dihydro-1-(phenylmethyl)-1H-indole as a
colorless oil.
(2) Using 0.76 g of the compound obtained in (1),
the procedure of Example 1 was followed to give 0.65 g
of 2,3-dihydro-5-[1-oxo-3-(piperidin-4-yl)propyl]-1-
(phenylmethyl)-1H-indole as a yellow oil.
Elemental analysis, for C23H28Nz0
Calcd.: C, 79.27; H, 8.10; N, 8.04
Found . C, 79.03; H, 8.05; N, 8.13
(3) Using 0.64 g of the compound obtained in (2),
the procedure of Example 2 was followed to give 0.66 g
of the free base of the title compound as a colorless
oil. This oil (0.66 g) was treated with an equivalent
of fumaric acid to give 0.75 g of the title fumarate as
colorless crystals melting at 153 to 156°C (decomp.).
_87_
J
Elemental analysis, for C3oH34N?O~C4H404
Calcd.: C, 73.62; H, 6.91; N, 5.05
Found . C, 73.65; H, 6.80; N, 5.00
Example 16
1-Acetyl-6-[1-oxo-3-[1-(phenylmethyl)piperidin-4-
yl]propyl]-1,2,3,4-tetrahydroquinoline fumarate
1 o Nc '~'.~-~ o Z ~
..
In 10 mQ of dichloromethane were dissolved 0.5 g
of 6-(1-oxo-3-[1-(phenylmethyl)piperidin-4-yl]propyl]-
1,2,3,4-tetrahydroquinoline (free base), 0.28 g of
acetic anhydride and 0.22 g of pyridine and the
solution was refluxed for 2 hours. The solvent and the
excess reagents were distilled off under reduced
pressure and the residue was dissolved in
dichloromethane. The solution was washed with 10~
sodium hydroxide and dried over anhydrous sodium
sulfate and the solvent was distilled off. This
residue was purified by chromatography (eluent; ethyl
acetate: ethanol = 20:1) to give 0.45 g of the free
base of the title compound as a colorless oil. This
oil, 0.45 g, was treated with an equivalent of fumaric
acid to give 0.53 g of the title fumarate as an
amorphous powder.
Elemental analysis, for C?~,H3~NZ02~C4H404
Calcd.: C, 69.21; H, 6.97; N, 5.38
Found . C, 69.23; H, 6.87; N, 5.40
Example 17
8-[1-Oxo-3-(piperidin-4-yl)propyl]-2,3,4,5-tetra-
hydro-1H-1-benzazepine
_p0_
~~~5~j~r
~~~iV fI
J
~~r''~- ~.-
0
Using 6.5 g of i~he compound A obtained in
Reference Exampel 4, the procedure of Example 1 was
followed to give a viscous oil and this oil was
crystallized from bexane to give 4.6 g of pale yellow
crystals melting at _L04 to 107°C.
Elemental analysis, for C18HZ6Nz0
Calcd.: C, 75.48; H, 9.15; N, 9.78
Found . C, 75.:?4; H, 9.09; N, 9.66
Example 18
Using the compounds obtained in Reference Examples
4, 6 and 7, the procedure of Example 1 was followed to
give compounds as oils as follows.
~tCH2) ~'
R' -N
~CCgy)m' ~NH ,
_89_
2~~~~=~ ~~
Compound ]t' m' R1 MolecularAnalysis
Calcd.
(Found)
No. formula
C H N
1 2 0 CZHS C ~ ai-Iz6Nz~7 5 . 9 . 9 . 7
4 8 15 8
75.22 9.17 9.69
2 2 0 C3H~ C, 9Hz~NzO7 5 . 9 . 9 . 3
9 6 3 9 2
75.78 9.25 9.12
3 2 0 C4H9 CzoH3oNz07 6 . 9 . 8 . 91
3 9 6 2
76.20 9.52 8.78
4 2 0 CSHiI CzyiszNzo76.78 9.82 8.53
76.69 9.81 8.55
2 0 CHZCHZPh Cz4H3oNz079.52 8.34 7.73
79.46 8.11 7.59
6 0 4 CH3 C,9HznNzO75.96 9.39 9.32
75.84 9.29 9.33
7 0 4 CZHS Czy-I3~NZo76.39 9.62 8.91
76.21 9.51 8.75
8 0 4 C3H~ Czl~i3zNzC76.78 9.82 8.53
76.53 9.74 8.41
9 4 U H C,AHz6Nz075.48 9.15 9.78
75.32 9.09 9.64
-90-
2~~~~f~'~
- 91 -
Example 19
Using the compound obtained in Examples 12, 17 or
18, the procedure of Example 13 was followed to give
the compounds as follows
U
~(CHZ) k'
r_
z
N CfI ~' ~I R
x~
to
-91-
~~~~~'-
b
~, ~ ~ .-. ~ (' n
z l0 N lD t0 lD .-1 .-I V' r-1 t~ .-i N In d' r--I l0 lD d' u7 d' 01 d' M M
O l0 d' l0 u) l0 lD l0 l!'7 l0 Lfl tD l0 00 I~ 00 t~ ~ 00 l~ l0 In u1 M
~ . . O O
u1 u1 In u1 u) u7 u7 u) In u'1 u1 u1 In ul n u1 rl r-I u1 u1 u7 u1 u1 ul
b
U
b '~' M M M t~ M N lD l~ ~p ~-1 lD 01 l0 O 00 O N l0 l0 N I~ M 1D N
U Ol Q1 Ol l~ 01 01 N N N M N .-1 .-1 M ~ In 01 01 r--I N M d' lC7 l0
lD l0 lp l0 l0 l0 l0 lD tD to l0 lD I~ I~ l0 l0 lD l0 I~ I~ l~ I~ h I~
O r-1 O ~i O 01 D1 In 01 '-1 01 M t~ Wit' .-'I M rl lD t~ 00 r-I u) N O
U O 01 O C~ O I~ 01 00 01 cT ~ OD N O N O N O N 01 L~ In '-1 O
.fir
OO t1 CJO t'' 00 I~ d' d' 'cT' d' l0 d' O O l~ I~ O O O 01 O O rl ,-1
t0 l0 l0 lD l0 l0 'lD l0 lD t0 ~p (~ f'~ lD lD (1 n I~ lp (~ I~ (~ (~
d ~ n
N N N N N N O M
~"I tf1 O * ~ * ~ -IC "~"' * ~ -I( '~-~ -It ~ * N* ~ ~ * ~ 'It ~ *
N d. N d- N ,'-I "'I r"I N z f~'7 N N N
zo zo zo ,~~o ~o Uo zo wo z zo zo zo
O d. O ~ O rv f I~ O 1 Iv O N ct
Cr7 th f''7 N ('J hJ M N N M w7 ~..~
~, s~ x ~ xx xx xx xx xx xx xx x xx xx xx
~.~
O O NU NU NU NU NU NU NU NU N NU NU NU
~ ~+-1 U ~ U ~ U ~ U ~ U ~ U ~ U ~ U ~ U U ~ U ~ U
o r-1 Chi M (~ M ,~ CT 00 M Q ul l0 u'7 I~
r. yn ~ o t.D m ~' ~D yo ~ ~ d~ ~.n M
.-a o .-, o .-, ,-~ ,-, ~ .-1 0 ,-~ o .-~ ,-, .-~ a,
I U I U I I I I I U I U I I I 1
C~ 01 N r-1 47 .-1 tT t'~ tD 01 N M O cN M lfl r-I
~ 'LWn b o m m err' ~o yD b ~ dmn o~
,.~ -- r.., -- ~ ,-i .~ ~ ,-1 ~ ~ .-a ~-1
M
x r~r M N
r-1
N
rx p ~~ ~~~ ~~ ~~ ~ ~ w
N x ~'y .r=.'
~~ ~ ~ ~ ~ U
U U ~ ~ L7 U t~ ~ x x x x x
U U U U U U U U U
x x
x x x :~ x x x x x x v v
0 0 0 « 0 0 0 0 0 0 0 0
N N N CV N N N N N N N N
b
O ~ ,-I N M ~3' tf7 ~D I~ Op O~ O .-i N
.-i ~1 rl
O
U
-92-
00N d'N M~ dll~ M00 00.-~d'l0 O~M 01I~ M01 N00 O1d' 010110M
M N 01 tD W M N l0 d' l11 M d' d' M
N .-i 01 ~f !1 N .-1 d' N N a1 N M N
d'
lfl Lf7 d' lfl 11117111 Ill W.lll'1In (n 111 111 lf7 ll7
IIl Lfl d' tf7 LCl ll U7 l1'7d' tIl Lfl 1I7
N
d' N 01 t~ l0 d' N f~ .-1 l0 dl f-I '--IM
l0 M M h lfl l0 01 00 lf1 l0 N N 00 r-I
l~ 01 O M IIl I~ O~ M 01 to tD 01 01 M
00 rl ~ d' Lf1 O~ 01 d' 01 l~ 01 D1 Ill
l~ n t~ C~ f~ h l~ I~ l0 I~ l0 lD lD t'
l~ 00 l~ l~ t'~ n (\ n l0 t~ l0 t0 I~
r-I 00 N '-I N e--1 00 .-1 N N 01 N 01 O
Ol n-1 Ol d' l~ 0p M 01 00 1I1 O d'
Lf1 00 01 1~ r-1 Lfl 00 t~ N .-1 O N N d'
N I~ t0 111 Ol M l0 111 00 rl O O 01 GO
. . . . . . . . . . . N
. . . . . . .
~--I .-i M O ,-I ~-I r--I O 00 r-1 l0 00 I~
.-I n-I M O O r-1 .-I O 1~ r-I l0 00
L~ I~ l~ t~ t' t~ I~ I'~ l0 I~ l0 lD ~ 00
l~ t~ I~ f~ l~ t~ t'~ l~ lD f~ l0 l0 lD lD
lD t0
O
O .-I O O N
O O O O O O O O Gv O U fz1 fs.lO
* * * * * * * * * * * * * *
N N N N N N N N N N N N N N
z z z z z z z z z z z zo zo zo
o o o o o o o o o' o o ~ ,.-i
t0 00 00 N V' tD 00 N ~ ~ -1
~
M M M M M M M M M M M M M M
x x x x x x x x x x x xx xx x
x x x x x x x x x x x
NU ;U NU U NU cU ~U ~iU c'vUNU NU NU x
ivU
U U U U U U U U U U U U U U
N
01 N O d' N h O O O 00 d O M 00
N d' ,~ h O 00 O CV l~ tf1 d' t~ lD N
T~ I~'~ ~ ~ ~"~ f~ f~ ~ 1~'~1~ f"'t t"
~
l~ O O M O d' 00 IW D N 00 Il1 00 lp
~-1
N d' ~ t~ O 00 Q1 ri 1C1 Lf1 M t0 LC7 N
O
In ~ .~ r-i ~ r~ ~ ~--I ~ .-i
M
Gz, ~ V ~' U
O
w
W PN PN W PN P ~ W x
N t~ x x x
U
U U U U U U U U U U U U
W
N
x
o, .-. U ~n r~
x x x x x
x
U U U x U U U x x x x x x x
O O O d' d' 'd' d' O d' d' d' d' d' d'
N N N O O ~~ 4 d' O O O O O O
M d' lfl l0 I~ OC7 01 O r-1 N M d' 111 lD
~--I .-1 .-I .-i ~~-I ~-I N N N N N N N
-93-
~J~'»~.1_~~'~q =~~'lJ~~.'i:.w:'''~.. ~7u':'L_~~.~ ~_t:::lri _ _ _..=r5-.. , ,
- _ _.. f I.".~. . ~~ i,1 ~ K-_, ....
to ~' to -.a' r1 to ~.t r~ ,~ a, ~a cri
M ct! M m ao to a0 n op t4 ' CO C7D
tr1 tn cr1 ,y~ w n u~ tn tn in ~ aye
M t'r7 M rJ' t O C3 CO ~'!' d0 ~~i l0 P~7
M tf' M rt~ tf'I ~' Wit' ~' ~/~ lt5 C~I 1"~
r t~ s_ r. tD Lo two t~ to n n
M ~ .-i t'''? .-a O, t~7
a,.ao ~-I ,-.a c~ 0 0 0
C, f~ N ~ N
. hp , .y.
W to CO to ~' l0 t~. t.b tp tp ~ ~ n
lp to -~ tO w.y0 ..... n ....
~ ~* ~ t* d y~k ~~* ~ ~1: ~
Z U ~ (~ 'c'~Q ~e.t p i'a O I ~ O
x ~;. x ~' J:.,:~
yU ~ ~U ~iU V ~ V r V
n O r~~ t-. f... r.)
-t n t~ -t' nt n
r-m--t ..-a ~ .. t ~ ,-t
t t I t i
tL) ft7 .-1 ~.1. ~!~ I ~.
.-i lt7 tt1 -,1~ fuel n
.-1 ..-I ~ t .-1
r,
°'
O ~ ~ '
i
r.~
_cn
W
S-.~ t..5 ~~ :'~ (,a ..... N
V U U I U iJ
1
f b
I
4a
Aev ~ .~ r~
x ~ x x ;~ U ~ .-r ~
d7
1 N ~ ~ U
4 O d, b .~
~ ~ ro
0 0 o t~t t'i. o d
a ~~ ~ U
U ~ ~ ~
. ..
t~ Ob d, p ;-..t N
N fV N t'7 M M
- 94 -
~ F~ G y
24205-912
Example 20
2,3-Dihydro-5-[1-oxo-3-(piperidin-4-yl)propylbenzofuran
hydrochloride
0
vHN~HCI
To 30 ml of concentrated hydrochloric acid was
added 5.00 g of 5-[3-(1-acetylpiperidin-4-yl)-1-
oxopropyl]-2,3-dihydrobenzofuran, and the mixture was
refluxed for 14 hours. The reaction mixture was left
standing for cooling, and was then made basic with a
dilute aqueous solution of sodium hydroxide, followed
by extraction with methylene chloride. Organic layers
were combined and dried over anhydrous sodium sulfate,
then the solvent was distilled off to leave 4.31 g
(100$) of 2,3-dihydro-5-[1-oxo-3-(piperidin-4-
yl)propyl]benzofuran (4). The solid matter thus
obtained was dissolved in methanol, treated with
hydrogen chloride and recrystallized from methanol -
ethyl acetate to give colorless needles, m.p. 203-205°C
(decomp.)
Elemental Analysis , for C16HZ1NOZ ~ HC1
Calcd.: C, 64.97; H, 7.50; N, 4.74
Found . C, 64.76; H, 7.64; N, 4.54
Example 21
2,3-Dihydro-5-[1-oxo-3-[1-(phenylmethyl)piperidin-4-
yl]propyl]benzofuran hydrochloride
D
To 30 ml of a mixture solution of tetrahydrofuran
-95-
24205-912
and ethanol {50/50=v/v) was added 1.52 g of 2,3-
dihydro-5-[1-oxo-3-(piperidin-4-yl)propyl]benzofuran,
to which was then added 1.06 g of potassium carbonate.
The resultant mixture was ice-cooled, and there was
added dropwise an ethanol solution {5 ml) of 0.96g of
benzyl bromide. The mixture was stirred for 22 hours
at room temperatures, then the solvent was distilled
off. To the residue was added water, which was
extracted with methylene chloride. Organic layers were
combined and dried aver anhydrous sodium sulfate, then
the solvent was distilled off. The residue was
purified by means of a silica gel column chromatography
(ethyl acetate) to give 1.13 g (55$) of 2,3-dihydro-5-
[1-oxo-3-[1-(phenylmethyl)piperidin-4-
yl]propylbenzofuran. The product was dissolved in
methanol, treated with hydrogen chloride, then
recrystallized from ethanol - ethyl acetate to give
colorless needles (1./4 hydrate), m.p. 143-144°C.
Elemental Analysis for CZgH2~NOZ.HC1.1/4Hz0:
Calcd.: C, 70.75; H, 7.36; N, 3.59
Found . C, 70.49; H, 7.26; N, 3.62
Example 22
7-[1-Oxo-3-[1-(phenylmethyl)piperidin-4-yl]propyl]-
2,3,4,5-tetrahydro-1H-3-benzazepine dihydrochloride
HM i[ ~~ ~ 2HC1
Under nitrogen atomosphere, 0.48 g (1.1 mmol.) of
3-methoxycarbonyl-7-[3-(1-benzoylpiperidin-4-yl)-1-yl)-
oxopropyl]-2,3,4,5-tetrahydro-1H-3-benzazepine obtained
in Reference Example 11 was dissolved in 5 ml of dry
chloroform. To the solution was added 0.3 ml (2.1
mmol.) of iodotrimethylsilane. The mixture was stirred
-96-
'"'rl~r~
24205-912
for 2.5 hours at 50°C. The reaction mixture was left
standing for cooling, to which was added 0.4 ml (10
mmol.) of methanol. To the resultant mixture were
added a dilute aqueous solution of sodium hydroxide and
an aqueous solution of sodium thiosulfate, followed by
extraction with dichloromethane. The extract was dried
over anhydrous sodium sulfate, then the solvent was
distilled off. The residue was dissolved in 15 ml of
dry tetrahydrofuran. To the solution was added 0.13 g
(3.4 mmol.) of lithium aluminum hydride, and the
mixture was refluxed for 5 hours. To the reaction
mixture was added water, then the solid matter was
filtered off. The filtrate was dried over anhydrous
sodium sulfate, then the solvent was distilled off.
The residue was dissolved in methanol and treated with
hydrogen chloride and the solvent was distilled off to
give a hydrochloride. To the hydrochloride further
added a mixture of 0.3 g (3 mmol.) of chromic acid, 0.3
ml of concentrated sulfuric acid and 10 ml of water-
acetone (1/1=v/v). The resultant mixture was stirred
for 24 hours at room temperatures. The reaction
mixture was poured into water, and it was made basic
with a dilute aqueous solution of sodium hydroxide,
followed by extraction with dichloromethane. The
extract was dried over anhydrous sodium sulfate, then
the solvent was distilled off. The residue was
purified by means of an alumina column chromatography
to give 0.31 g (76~;) of 7-[1-oxo-3-[1-
(phenylmethyl)piperidin-4-yl]propyl]-2,3,4,5-
tetrahydro-1H-3-benzazepine. The product was dissolved
in methanol and treated with 3 N methanolic
hydrochloric acid to give dihydrochloride as an
amorphous powder.
Elemental Analysis, for CZSHs2Nz0 ~ 2HC1 ~ 2 . 5H20:
Calcd.: C, 60.'72; H, 7.95; N, 5.66
-97_
i~ ~e~
i
~7 .,~ ::~ :v .i
24205-912
Found . C, 60.85; H, 8.24; N, 5.51
Example 23
3-Methyl-7-[1-oxo-3-[1-(phenylmethyl)piperidin-4-yl]-
propyl]-2,3,4,5-tetrahydro-1H-3-benzazepine
dihydrochloride
a
Ye-Y ~~ ~ 2HCI
,,
In 40 ml of toluene was dissolved 1.17 g {2.6
mmol.) of 3-methoxycarbonyl-7-[3-(1-benzoylpiperidin-4-
yl)-1-oxopropyl]-2,3,4,5-tetrahydro-1H-3-benzazepine.
To the solution were added 7 ml of ethylene glycol and
10 mg of p-toluenesulfonic acid, and the mixture was
refluxed for 2.5 hours. To the reaction mixture was
added a saturated aqueous solution of sodium hydrogen
carbonate, which was subjected to extraction with
diethyl ether. The extract was dried over anhydrous
sodium sulfate, then the solvent was distilled off.
The residue was purified by means of a silica gel
column chromatography to give 1.22 g {94~s) of 7-[2-[2-
(1-benzoylpiperidin-4-yl)ethyl]-1,3-dioxoran-2-yl]-3-
methoxycarbonyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
1.03 g (2.1 mmol.) of the compound obtained above was
dissolved in 15 ml of dry tetrahydrofuran, to which was
added 0.25 g {6.5 mmol.) of lithium aluminum hydride.
The reaction mixture was refluxed for 3 hours, and there
was added water, followed by filtration. The filtrate
was dried over anhydrous sodium sulfate, then the
solvent was distilled off. The residue was dissolved
in tetrahydrofuran, to which was added 5.6 ml of 1N-
HC1, and the mixture was stirred for 14.5 hours at room
temperature. The reaction mixture was made basic with
a dilute aqueous solution of sodium hydroxide, followed
-98_
~~'~~ ~~~1
24205-912
by extraction with dichloromethane. The extract
solution was dried over anhydrous sodium sulfate, then
the solvent was distilled off. The residue was
dissolved in methanol and the solution was treated with
hydrogen chloride to give a dihydrochloride, which was
then recrystallized from ethanol - ethyl acetate to
give 0.65 g (67~) of colorless needles, m.p. 190-193°C.
Elemental Analysis for C26H34N2~ ~ 2HC1 ~ H20:
Calcd.: C, 64.86; H, 7.95; N, 5.82
Found . C, 64.78; H, 7.90; N, 5.78
Example 24
2,3-Dihydro-6-[1-oxo-3-{piperidin-4-yl)propyl]-1H-
indole
H
H 0
(1) To a mixture of 25 g of 2,3-dihydro-1-
trifiuoroacetyl-indale, 25 g.of 3-(1-acetylpiperidin-4-
indole)propionic acid chloride and 120 ml of carbon
disulfide was added 56 g of anhydrous aluminum chloride
at room temperatures, then the mixture was refluxed for
hours. The reaction mixture was treated in a
25 manner similar to Reference Example 1-(3) to give 9.0 g
of a mixture of 6-[3-(1-acetylpiperidin-4-yl)-1-
oxopropyl]-2,3-dihydro-1-trifluoroacetyl-1H-indole and
5-[3-{1-acetylpiperidin-4-yl)-1-oxopropyl]-2,3-dihydro-
1-trifluoroacetyl-1H-indole as a pale yellow oily
30 product.
(2) The oily product obtained in (1) was subjected to
reaction similar to Example 1 to give 2,3-dihydro-6-1-
oxo-3-(piperidin-4-yl)propyl]-1H-indole
dihydrochloride. A mixture of this dihydrochloride and
2,3-dihydro-5-1-oxo-3-(piperidin-4-yl)propyl]-1H-indole
-99-
P' 4~ ~ ri r~
~,~ erg c3 ~:~
dihydrochloride was subjected to recrystallization
twice from methanol - ethyl acetate to give 2.5 g of
dihydrochloride of the above-titled compound as
colorless powder, m.p. 146-148°C. The powdery compound
thus obtained was dissolved in water, whose pH was
adjusted to about 10 with a 7.0~ sodium hydroxide
solution, which was subjected to extraction with
dichloromethane. The extract solution was dried over
anhydrous sodium sulfate, and the solvent was distilled
off under reduced pressure to give 1.8 g of the above-
titled compound as a pale yellow oily product.
Elemental Analysis, for C16F3zzNz0~
Calcd.: C, 74.38; H, 8.58; N, 10.84
Found . C, 74.32; H, 8.66; N, 10.74
Example 25
2,3-Dihydro-6-[1-oxo-3-[1-(phenylmethyl)piperidin-4-
yl]propyl]-1H-indole furnarate
C02H
~~ .
Using 0.5 g of the compound obtained in Example
24, the procedure of Example 13 was followed to give
0.55 g of the title compound as colorless crystals,
m.p. 157-158°C.
Elemental Analysis for Cz3Hz8NZO.C4H40,,:
Calcd.: C, 69.81; H, 6.94; N, 6.03
Found . C, 69.65; H, 6.87; N, 5.76
Example 26
9-[1-Oxo-3-(piperidi.n-4-yl)propyl]-1,2,3,4,5,6-
hexahydro-1-benzazocine
~_
-100-
Using 1-ethoxycarbonyl-1,2,3,4,5,6-hexahydro-1-
benzazocine, the procedure of Reference Example 2-(2)
was followed to give a residue. The residue was
subjected to similar reaction to Example 1 to give the
title compound as a pale yellow oily product.
Elemental Analysis, :for Cl9HzaNzO~
Calcd.: C, 75.95; Ii, 9.39; N, 9.33
Found . C, 75.7:3; H, 9.38; N, 9.10
Example 27
9-[1-Oxo-3-[1-(pheny:Lmethyl)piperidin-4-yl]propyl]
1,2,3,4,5,6-hexahydro-1-benzazocine fumarate
CaZH
~' ~'~' ~-J ~ H0 ~
2
Using 9-[1-oxo-3-(piperidin-4-yl)propyl]-
1,2,3,4,5,6-hexahydro-1-benzazocine, the procedure of
Example 13 was followed to give the title compound as
colorless crystals.
Elemental Analysis, for Cz6I-I;",NzO~C,,H,,04: ,
Calcd.: C, 71.1:?; H, 7.56; N, 5.53
Found . C, 70.98; I-I, 7.61; N, 5.42
Example 28
1-Acetyl-8-[1-oxo-3-[1-(phenyl.methyl)piperidin-4-
yl]propyl]-2,3,4,5-tetrahydro-1H-1-benzazepine
-~' N ' \
r
Ac O
Using 0.3 g of 8-[1-oxo-3-[1-
(phenylmethyl)piperidin-4-yl]propyl]-2,3,4,5-
tetrahydro-1H-1-benzazepine, which is a free base of
the compound obtained in Example 19 compound No. 16,
the procedure of Example 16 was followed to give 0.21 g
of the title compound as a colorless powder, m.p. 115-
-101-
d l
116°C.
Elemental Analysis, :Eor CZ~H3~,NZUz
Calcd~.: C, 77.48; H, 8.19; N, 6.69
Found . C, 77.2:1; H, 7.98; N, 6.56
Example 29
3,4-Dihydro-6-[1-oxo-3-(piperidin-4-yl)propyl]-2H-1-
benzothiopyran hydrochloride
o-
NH 'HC1
S
Using 2.5 g of i~he compound obtained in Reference
Example 12, the procedure of Example 1 was followed to
give 2.4g of the title compound as a colorless powder,
m.p. 196-199°C.
Elemental analysis, for CZ4Hz9NOS~HC1:
Calcd.: C, 62.6.'i; H, 7.42; N, 4.30
Found . C, 62.61; H, 7.33; N. 4.27
Example 30
3,4-Dihydro-6-[1-oxo--3-[1-(pluenylmethyl)piperidin-4-
yl ] propyl ] -2H-1-benzothiopyran hydrochloride
I
-IIC1
S -'~.-~ N . i
Using 0.838 of t:he compound obtained in Example
29, the procedure of Example 2 was followed to give
l.Og of the title compound as a colorless powder, m.p.
186-188°C.
Elemental analysis , f_or C24H?9NOS ~ HC1
Calcd.: C, 69.29; H, 7.27; N, 3.37
Found . C, 69.37_; H, 7.22; N, 3.27
-102-
2 0 5 5 9 4 7 24205-912
Example 31
8-[1-Oxo-3-(piperidin-4-yl)propyl]-2,3,4,5-tetrahydro-
1H-2-benzazepine dihydrochloride (A) and 7-(1-oxo-3(piperdine-4-
yl)propyl]-2,3,4,5-tetrahydro-iH-2-benzazepine dihydrochloride (B)
o-
NH
HN HN NH
~ 2HC 1
~2HCL
(A) (g)
Using 5.0 g of 2-acetyl-2,3,4,5-tetrahydro-1H-2-
benzazepine, the procedure of Reference Example 1 was followed to
give 4.7 g of a viscous oil.
Using 4.5 g of the oil, the procedure of Example 1 was
followed to give 3.3 g of a pale yellow solid. The solid was
recrystallized from methanol to give the title compound (A) as
colorless powder, m.p.>300oC. And, the title compound (B) was
obtained as amorphous powder by concentrating the mother liquor
obtained in the recrystallization of the compound (A) mentioned
above.
Elemental analysis, for C18H26N20.2HC1:
Calcd ~ C, 60.17; H, 7.85; N, 7.80.
Found r C, 59.95; H, 7.98; N, 7.77.
Example 32
8-[1-Oxo-3-[1-(phenylmethyl)piperdin-4-yl]propyl]-2-
(phenylmethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine dihydrochloride
(A) and 8-[1-oxo-3-[1-(phenylmethyl)piperidin-4-yl]propyl]-
103
~~~~947
24205-912
2,3,4,5-tetrahydro-1H-2.-benzazepine dihydrochloride (B)
r:
N I ~ Y ~ ~ IIN I
O O
(A) (B)
Using 1.5 g of 8-(1-oxo-3-(piperdin-4-yl)propyl~-
2,3,4,5-tetrahydro-1H-2-benzazepine dihydrochloride obtained in
Example 31, the procedure of Example 2 was
103a
ta:'
. <:
~~~r ~-;
r5a~i~'"'~'T:~'.J~.. :~iL:'Ti~ ~-.~: :~ ._..._..i.'.: r "__,v_...~7~...
r ~ ~ _ r n
24205-912
followed to gzve 0.5 g of the title compound (A) a$ an
amorphous powder and 0.1 g of the title compound (B) as
an amorphous powder.
8- [ 1--Oxo-3- ( ~.- ( phez~ylmethyl ) pipexidin-4-
yl}prvpylJ-2-(phenyl.methyl)-2,3,4,5-tetrahydro-LH-.2-
benzazepine dxhydrochloride (A)
Elemental. analysis, for C3zH38N20~2HC1:
Calcd.: C, 71.23; H, 7.47; N, 5.19.
Found . C, 66.72; H, 7.69; N, 6.01.
1Q 8-(I-Oxo-3-(1-(phenylmethyl)piperidin-4-
y).)propyl],2,3,4,5-tetrahydro-IH-2-benzazepine
dihydxoohloride (B)
Elemental analysis, fox C25H32N20~ 2HC1:
calCd.: C, 66.81; Fi, 7.62; N, 6.23.
L5 Found . C, 66.72; H, 7.69; N, 6.01.
Example 33
8-Chloro-S-[I-axo_~~-(7.-(phenylmethyl)piperidin-4-
Yllpropy.~J-Z,2,3,4-tetrahydxoisor~u.inoline
Dih~rdzochlozi.de
2fl cl
0 f CH z CH 2~-CH Z ~ ~
25 To a solution of 5 . 99 gg ( I3 . 22 nunol ) of the,
compound obtained in Reference Examphe Z4 in 198 ml of
methanol was added 9a ml of lN~~queous NaOH. THe
mixture ~~aas stirred at 60°C for 5 hours. After removal
of methanol under xQduced pressure, the aqueos residue
3Q was extracted with dichl~~ro~methane. The extracts were
dried over anhydrous sodium sulfate and the solvent was
distilled off. The residue ,vas purified by means of a
silica gel column chromatography (eluent; ethyl.
acetate:methanol - 7:3;v/v)) to give 2.59 g of 5-(3-(1-
35 benzoylpipexidin-4-yl)-1-~oxr~propyl]-8-chloro-i,2,3,4-
- 104 -
e~ ~ ~~ ~~ T~
v
d~~Lil~i~~ .j~4'-.fiiT==~~F-,i i:_.~_'~ =:j:-:~h L'=:_._____.. i ,.'2.v~'v '
_. __
_,
24205-912
tetrahydro~.soquinol.~ne .
To a solut~.on of i.23 g (3.0 mmol) of the compound
obtained above in 10 ml of methanol was added 0.75 ml
of 4N methanoli c HC1 at: 5 °C and t~~;e solvent was
distilled otf. To the residual oil was added 60 ntl of
toluene, 8.z4 ml of ethylene glycol, and 57 mg of p-
toluenesulfonic acid monohydrate. The mixture was
refluxed for 2 hours. To the reaction mixture was
added a saturated aquecws solution of NaHCJz, which was
subjected to extraction t,~'ith dichloromethane. The
extracts were dried over anhydrous sodium sulfate, then
the solvent removed under reduced pressure. The
residue was purified by means of a silica gel. column
chromatography (eluent; ethyl acetate:
7.5 methanol=7:3(v/v) to give 1.31 g of 5-[2-[2-(I,
benaoylpiperidi.n-4-yl.)ethyl]-1,3-dioxoran-2-y1~~8--
chloro-3.,2,3,4-tetrahydroisoquinoline.
Under nitrogen atmosphere, to a solution of 455 mg
( 1 . 0 mg ~ o~E the compound obtained above in .~0 ml of dry .
tetrahydrofuran was added 127u1 of chldro
trimethylsilane at 5°C and the mixture was stirred at
room temperature for 1 hour. Then to the reaction
mzxture was added 190 mg of lithium aluminum hydride
and thQ mi.~ture was rafluxed for 2.5 hours. water was
Z5 added to mia~ure and the .resul ti ng precipitate was
ze;noved by fiJ.tration . The fil.txate was dried oven
anhydrous sodium sulfate, and the solvent was removed
under reduced pressure. A z~ixture of the residue and 5
ml of 1N aqueous HC1 :ire S ml of tetrahydrofuran saes
heated at 60°C for 3 hours. The reaction mixture was
made basic with a dilt~tE, aqueous NaOH, followed by
extraction with dichloromethane.~ The extract was dried
over anhydrous sodium szxlfate, then the solvent was
removed under reduced p~°essure to give Z00 mg of a
colorless oil, which wa:: treated w~.th 4N-methanolic HCl
- 105 -
r.. nr ~ »
2~3~~~~
24205-912
(2 equivalent) to give 205 mg of the title compound as an amor-
phous powder.
Elemental analysis, for C29,H29C1N20.2HC1:
Calcd.: C, 61.35; H, 6.65; N, 5.96.
Found . C, 61.42; H, 6.69; N, 5.91.
- 106 -
24205-912
Formulation Example 1
(1) 6-[3-[1-(Phenylmethyl)piperidin-4-yl]-1-
oxopropyl]-1,2,3,4-tetrahydroquinoline bihydrochloride
(the compound obtained in Example 2) 1 g
(2) Lactose 197 g
(3) Corn starch 50 g
(4) Magnesium stearate 2 g
(1), (2) and 20 g of corn starch were blended and
the mixture was granulated with a paste prepared from
g of corn starch and 25 ml of water. To this
granular product were added 15 g of corn starch and (4)
and the resulting composition was compression-molded to
provide 2000 tables each measuring 3 mm in diameter and
15 containing 0.5 mg of (1).
Formulation Example 2
(1) 6-[3-[1-(Phenylmethyl)piperidin-4-yl]-1-
oxopropyl]-1,2,3,4-tetrahydroquinoline dihydrochloride
(the compound obtained in Example 2) 2 g
(2) Lactose 196 g
(3) Corn starch 50 g
(4) Magnesium stearate 2 g
(1), (2) and 20 g of corn starch were blended and
the mixture was granulated with a paste prepared from
15 g of corn starch and 25 ml of water. To this
granular product were added 15 g of corn starch and (4)
and the resulting composition was compression-molded to
provide 2000 tablets each measuring 5 mm in diameter
and containing 1 mg of (1).
-107-
2~~~r~~r~
24205-912
Formulation Example 3
(1) 8-[1-Oxo-3-[1-(Phenylmethyl)piperidin-4-
yl]propyl]-2,3,4,5-tetrahydro-1H-1-benzazepine fumarate
(the compound obtained in Example 19 compound No. 16)
1 g
(2) Lactose 197 g
(3) Corn starch 50 g
(4) Magnesium stearate 2 g
(1), (2) and 20 g of corn starch were blended and
the mixture was granulated with a paste prepared from
g of corn starch and 25 ml of water. To this
granular product were added 15 g of corn starch and {4)
and the resulting composition was compression-molded to
provide 1000 tablets each measuring 3 mm in diameter
15 and containing 1.0 mg of (1).
Formulation Example 4
(I) 7-[1-Oxo-3-[1-{phenylmethyl)piperidin-4
yl]propyl]-2,3,4,5-tetrahydro-1H-3-benzazepine
dihydrochloride (the compound obtained in Example 22)
2 g
(2) Lactose 196 g
(3) Corn starch 50 g
(4) Magnesium stearate 2 g
(1), (2) and 20 g of corn starch were blended and
the mixture was granulated with a paste prepared from
15 g of corn starch and 25 ml of water. To this
granular product were added 15 g of corn starch and {4)
and the resulting composition was compression-molded to
provide 2000 tablets each measuring 5 mm in diameter
and containing 1 mg of {1).
Formulation Example 5
8-[1-Oxo-3-[1-(phenylmethyl)piperidin-4-yl]propyl]-
2,3,4,5-tetrahydro-1H-1-benzazepine fumarate (the
-108-
24205-912
compound obtained in Example 19, compound No. 16) (2 g)
and 1.25g of mannitol were dissolved in 500 mQ of
distilled water, pH was adjusted to 5.6 to 7 with O.1N
NaOH and the total amount of the solution was made up
to 1000 mQ. The solution thus obtained was sterilized
by filtration through a filter of 0.2um. The resulting
solution was distributed to provide 1000 of 1mQ-
ampoules.
Experimental Example
The cholinesterase inhibitory activity of the
compound of the present invention was assayed with
(acetyl-[3H])-acetylc:holine. Thus, using the S1
fraction of a homogenate of male Wistar rat cerebral
cortex as the cholinesterase source, (acetyl-[3H]j-
acetylcholine and the compound of the invention were
added as the substrate and the test substance,
respectively, and the mixture was incubated for 30
minutes. After the i:eaction was terminated, a toluene-
based scintillant was added and, after shaking, the
reaction product [3H]-acetic acid which was transferred
to the toluene layer was determined with a
scintillation counter_ to estimate the cholinesterase
activity.
The cholinesterase inhibitory activity of the test
compound was expressed in 50~ inhibitory concentration
{ICSO). The cholinesterase inhibitory activity of
physostigmine was also determined by the same
procedure.
The results are shown in Table 1.
_I09_
2~5~ J ~~
24205-912
[Table 1]
Compound Acetylcholinesterase inhibitory
(Example No.) activity ICSO (~M)
2 0.014
3 0.12
4 0.010
6-A 0.054
6-B 0.054
8-A 0.024
8-B 0.036
10 0.16
13 0.020
14 0.010
15 0.068
16 0.014
19-4 0.076
19-5 0.059
19-7 0.050
19-8 0.016
19-9 0.064
19-11 0.011
19-12 0.022
19-13 0.029
19-14 0.047
19-I5 0.028
19-16 0.102
19-17 0.081
19-20 O.I25
19-21 0.145
21 0.028
22 0.0076
23 0.0065
25 0.113
27 0.127
PhysostigminE~ 0.22
The above results indicate that the compound of
the present invention has excellent cholinesterase
inhibitory activity.
The compound of the present invention has effects
on the central nervous system of mammalian animals and
-110 -
,,. B
24205-912
exhibits potent cholinesterase inhibitory activity.
Therefore, the compound can be used for the prevention
and treatment of senile dementia, Alzheimer's disease,
Huntington's chorea and other diseases related to brain
dysfunction and is, therefore, of value as a
medicament.
-111-
